Coating for implantable devices and a method of forming the same

ABSTRACT

Coatings for implantable devices or endoluminal prosthesis, such as stents, are provided, including a method of forming the coatings. The coatings can be used for the delivery of an active ingredient or a combination of active ingredients.

CROSS-REFERENCE

This is a divisional of U.S. patent application Ser. No. 11/506,656,which is a divisional application of U.S. patent application Ser. No.10/751,289, which is a continuation application of U.S. Pat. No.6,790,228 filed on Dec. 28, 2000 and issued on Sep. 14, 2004.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to coatings and methods of forming the coatings onimplantable devices or endoluminal prostheses, such as stents.

2. Description of the Background

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to radially press againstthe atherosclerotic plaque of the lesion for remodeling of the vesselwall. The balloon is then deflated to a smaller profile to allow thecatheter to be withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation ofintimal flaps or torn arterial linings which can collapse and occludethe conduit after the balloon is deflated. Vasospasms and recoil of thevessel wall also threaten vessel closure. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may require another angioplasty procedure or a surgicalby-pass operation. To reduce the partial or total occlusion of theartery by the collapse of arterial lining, and to reduce the chance ofthe development of thrombosis and restenosis, an expandable,intraluminal prosthesis, one example of which includes a stent, isimplanted in the lumen to maintain the vascular patency.

Stents are used not only as a mechanical intervention but also as avehicle for providing biological therapy. As a mechanical intervention,stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically stents arecapable of being compressed, so that they can be inserted through smallcavities via catheters, and then expanded to a larger diameter once theyare at the desired location. Examples in the patent literaturedisclosing stents which have been successfully applied in PTCAprocedures include stents illustrated in U.S. Pat. No. 4,733,665 issuedto Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S. Pat.No. 4,886,062 issued to Wiktor. Mechanical intervention via stents hasreduced the rate of restenosis as compared to balloon angioplasty; butrestenosis is still a significant clinical problem with rates rangingfrom 20-40%. When restenosis does occur in the stented segment, itstreatment can be challenging, as clinical options are more limited ascompared to lesions that were treated solely with a balloon.

Biological therapy can be achieved by medicating the stents. Medicatedstents provide for the local administration of a therapeutic substanceat the diseased site. In order to provide an efficacious concentrationto the treated site, systemic administration of such medication oftenproduces adverse or toxic side effects for the patient. Local deliveryis a preferred method of treatment in that smaller total levels ofmedication are administered in comparison to systemic dosages, but areconcentrated at a specific site. Local delivery thus produces fewer sideeffects and achieves more favorable results.

One proposed method for medicating stents disclosed seeding the stentswith endothelial cells (Dichek, D. A. et al. Seeding of IntravascularStents With Genetically Engineered Endothelial Cells; Circulation 1989;80: 1347-1353). Briefly, endothelial cells were seeded onto stainlesssteel stents and grown until the stents were covered. The cells weretherefore able to be delivered to the vascular wall where they providedtherapeutic proteins. Another proposed method of providing a therapeuticsubstance to the vascular wall included use of a heparin-coated metallicstent, whereby a heparin coating was ionically or covalently bonded tothe stent. Significant disadvantages associated with the aforementionedmethod includes significant loss of the therapeutic substance from thebody of the stent during delivery and expansion of the stent, anabsolute lack of control of the release rate of the proteins from thestent, and the inherent limitation as to the type of therapeuticsubstance that can be used.

Another proposed method involved the use of a polymeric carrier coatedonto the surface of a stent, as disclosed in U.S. Pat. No. 5,464,650issued to Berg et al. Berg disclosed applying to a stent body a solutionwhich included a specified solvent, a specified polymer dissolved in thesolvent, and a therapeutic substance dispersed in the blend. The solventwas allowed to evaporate, leaving on the stent surface a coating of thepolymer and the therapeutic substance impregnated in the polymer. Amongthe specified, suitable choices of polymers listed by Berg, empiricalresults were specifically provided for poly(caprolactone) andpoly(L-lactic acid). The preferred choice of mutually compatiblesolvents included acetone or chloroform. As indicated in Berg, stentswhere immersed in the solution 12 to 15 times or sprayed 20 times. Theevaporation of the solvent provided a white coating. A white colorationis generally indicative of a brittle coating. A brittle coating is anundesirable characteristic, since portions of the coating typicallybecome detached during stent expansion. Detachment of the coating causesthe quantity of the therapeutic substance to fall below a thresholdlevel sufficient for the effective treatment of a patient.

It is desirable to improve the adhesion or retention of the polymericcoating to the surface of a prosthesis, e.g., stent. It is alsodesirable to be able to increase the quantity of the therapeuticsubstance carried by the polymeric layer without perturbing themechanical properties of the coating, such as inadequate coatingadhesion, or significantly increasing the thickness of the coating.

It is additionally desirable to provide an improved polymeric coatingthat is susceptible to delivery and expansion with a prosthesis withoutsignificant detachment from the surface of the prosthesis. An improvedpolymeric coating is also needed which allows for a significant controlof the release of the therapeutic substance.

It may also be advantageous to maintain the concentration of thetherapeutic substance at a therapeutically acceptable level for aprolonged duration of time. Depending on the physiological mechanismtargeted, the therapeutic substance may be required to be released atthe target site for an extended duration of time. Accordingly, it isdesirable to provide a coating which can maintain the residence time ofa substance at a therapeutically useful concentration for an effectiveduration of time.

SUMMARY OF THE INVENTION

In accordance with one aspect of the present invention, a prosthesis isprovided, such as a balloon-expandable stent or a self-expandable stent,which includes a coating having a reservoir region carrying an activeingredient, e.g., actinomycin D or taxol. A primer region, free from anyactive ingredients, can be disposed between the reservoir region and thesurface of the prosthesis. The primer can act as an intermediary tielayer between the surface of the prosthesis and the reservoir region.The primer and reservoir regions can be made form the same polymericmaterial or different polymeric materials. The prosthesis canadditionally include a barrier region disposed on a selected portion ofthe reservoir region for reducing the rate at which the activeingredient is released. In one embodiment, the barrier layer containsinorganic particles. Examples of suitable polymeric materials for theprimer layer include polyisocyanates, unsaturated polymers, aminecontent polymers, acrylates, polymers containing a high content ofhydrogen bonding groups, and inorganic polymers. Biocompatible polymerscan be used not only for the primer region, but also for the reservoirregion. One examples of a biocompatible polymer includes ethylene vinylalcohol copolymer.

In accordance with another aspect of the present invention, a method isprovided for forming a coating for an implantable device comprisingforming a primer on at lease a selected portion of a surface of theimplantable device and forming a reservoir region containing an activeingredient on at least a selected portion of the primer. The primer canprovide an adhesive tie layer between the surface of the implantabledevice and the reservoir region. In one embodiment, the method canadditionally include forming a barrier layer on at lease a selectedportion of the reservoir region for reducing the rate at which theactive ingredient is released from the reservoir region.

In one embodiment, the act of forming the primer comprises applying acomposition to a selected portion of the surface of the implantabledevice wherein the composition includes a thermoplastic polymer added toa solvent, and heating the composition applied to the implantable deviceto a temperature greater than about the glass transition temperature andless than about the melting temperature of the polymer.

In accordance with another embodiment, the act of forming the primercomprises applying a composition to a selected portion of the surface ofthe implantable device, wherein the composition comprises an inorganicpolymer added to a solvent, and significantly removing the solvent toform the primer.

In accordance with another embodiment, the act of forming the primercomprises applying a composition to a selected portion of the surface ofthe implantable device, wherein the composition comprises a polymeradded to a solvent, and heating the composition applied to the selectedportion of the surface of the implantable device to a temperature abovethe glass transition temperature of the polymer.

In accordance with another embodiment, the act of forming the primercomprises applying a composition to a selected portion of the surface ofthe implantable device, wherein the composition comprises a prepolymerand an initiator, e.g., a free radical or UV initiator. The compositionis then exposed to a condition such as UV radiation or heat topolymerize the prepolymer.

In accordance with another aspect of the present invention, a coatingfor a stent is provided containing a first active ingredient and asecond active ingredient, wherein the rate of release of the firstactive ingredient is slower than the rate of release of the secondactive ingredient. The coating can be made from a polymeric materialsuch as an ethylene vinyl alcohol copolymer. The coating can include afirst region containing the first and second active ingredients, and asecond region, free from any active ingredients, located between thefirst region and the surface of the stent. The second region increasesthe ability of the coating to be retained by the stent.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1A illustrates a fluid on a solid substrate having a contact angleΦ₁;

FIG. 1B illustrates a fluid on a solid substrate having a contact angleΦ₂;

FIGS. 2A-2E illustrate a coating in accordance with some of theembodiment of the present invention;

FIGS. 3A and 3B illustrate a coating having different layers;

FIG. 4 graphically illustrates elution profiles for stents with acoating of ethylene vinyl alcohol copolymer impregnated with vinblastinemade according to Example 4;

FIG. 5 graphically illustrates in vitro experimental data, in accordancewith Example 15, showing affects of actinomycin D, mitomycin, anddocetaxel on smooth muscle cell proliferation;

FIG. 6A is a picture of a histology slide of a coronary vessel from thecontrol group in accordance with Example 16;

FIG. 6B is a picture of a histology slide of a coronary vessel from theactinomycin D group in accordance with Example 16

FIG. 7A is a picture of a histology slide of a coronary vessel from thecontrol group in accordance with Example 26; and

FIG. 7B is a picture of a histology slide of a coronary vessel from theactinomycin D group in accordance with Example 26.

DETAILED DESCRIPTION OF THE EMBODIMENTS Composition for Forming thePrimer Layer

The embodiments of the composition for a primer layer are prepared byconventional methods wherein all components are combined, then blended.More particularly, in accordance to one embodiment, a predeterminedamount of a polymer or a prepolymer is added to a predetermined amountof a solvent or a combination of solvents. The mixture can be preparedin ambient pressure and under anhydrous atmosphere. If necessary, a freeradical or UV initiator can be added to the composition for initiatingthe curing or cross-linking of the prepolymer. Heating and stirringand/or mixing can be employed to effect dissolution of the polymer intothe solvent.

“Polymer,” “poly,” and “polymeric” are defined as compounds that are theproduct of a polymerization reaction and are inclusive of homopolymers,copolymers, terpolymers etc., including random, alternating, block, andgraft variations thereof. The polymers should have a high capacity ofadherence to the surface of an implantable device, such as a metallicsurface of a stent. Stainless steel, such as 316L, is a commonly usedmaterial for the manufacturing of a stent. Stainless steel includes achromium oxide surface layer which makes the stent corrosion resistantand confers, in large part, biocompatibility properties to the stent.The chromium oxide layer presents oxide, anionic groups, and hydroxylmoieties, which are polar. Consequently, polymeric materials with polarsubstituents and cationic groups can adhere to the surface.Representative examples of suitable polymeric material includepolyisocyanates, unsaturated polymers, high amine content polymers,acrylates, polymers with high content of hydrogen bonding groups, silanecoupling agents, titanates and zirconates.

Representative examples of polyisocyanates include triisocyanurate,alphatic polyisocyanate resins based on hexamethylene diisocyanate,aromatic polyisocyanate prepolymers based on diphenylmethanediisocyanate, polyisocyanate polyether polyurethanes based ondiphenylmethane diisocyanate, polymeric isocyanates based on toluenediisocyanate, polymethylene polyphenyl isocyanate, and polyesterpolyurethanes.

Representative examples of unsaturated polymers include polyesterdiacrylates, polycaprolactone diacrylates, polyester diacrylates,polytetramethylene glycol diacrylate, polyacrylates with at least twoacrylate groups, polyacrylated polyurethanes, and triacrylates. With theuse of unsaturated prepolymers a free radical or UV initiator can beadded to the composition for the thermal or UV curing or cross-linkingprocess. For thermal curing, examples of free radicals initiators arebenzoyl peroxide; bis(2,4-dichlorobenzoyl) peroxide; dicumyl peroxide;2,5-bis(tert-butyl peroxy)-2,5-dimethyl hexane; ammonium persulfate, and2,2′-azobisisobutyronitrile. As is understood by one of ordinary skillin the art, each initiator requires a different temperature to inducedecomposition. For UV curing, examples of initiators include2,2-dimethoxy-2-phenylacetophenone; 1-hydroxycyclohexyl phenyl ketone;benzoin ethyl ether; and benzophenone. These initators can be activatedby illumination with a medium pressure Hg bulb that contains wavelengthsbetween 250 and 350 nm.

Representative examples of high amine content polymers includepolyethyleneamine, polyallylamine, and polylysine.

Representative examples of acrylates include copolymers of ethylacrylate, methyl acrylate, butyl methacrylate, methacrylic acid, acrylicacid, and cyanoacrylates.

Representative examples of high content of hydrogen bonding grouppolymers include polyethylene-co-polyvinyl alcohol, epoxy polymers basedon the diglycidylether of bisphenol A with amine crosslinking agents,epoxy polymers cured by polyols and lewis acid catalysts, epoxyphenolics, epoxy-polysulfides, ethylene vinyl acetate, melamineformaldehydes, polyvinylalcohol-co-vinyl acetate polymers,resorcinol-formaldehydes, urea-formaldehydes, polyvinylbutyral,polyvinylacetate, alkyd polyester resins, acrylic acid modified ethylenevinyl acetate polymers, methacrylic acid modified ethylene vinyl acetatepolymers, acrylic acid modified ethylene acrylate polymers, methacrylicacid modified ethylene acrylate polymers, anhydride modified ethyleneacrylate copolymers, and anhydride modified ethylene vinyl acetatepolymers. Representative examples of silane coupling agents include3-aminopropyltriethoxysilane and(3-glydidoxypropyl)methyldiethoxysilane.

Representative examples of titanates include tetra-iso-propyl titanateand tetra-n-butyl titanate.

Representative examples of zirconates include n-propyl zirconate andn-butyl zirconate.

Biocompatible polymers can also be used for the primer material.Examples of biocompatible primers include poly(hydroxyvalerate),poly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide),poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone,polyorthoesters, polyanhydrides, poly(glycolic acid), poly(D,L-lacticacid), poly(glycolic acid-co-trimethylene carbonate), polyphosphoesters,polyphosphoester urethanes, poly(amino acids), cyanoacrylates,poly(trimethylene carbonates), poly(iminocarbonate),copoly(ether-esters) (e.g. PEO/PLA), polyalkylene oxalates,polyphosphazenes and biomolecules such as fibrin, fibrinogen, cellulose,starch, collagen and hyaluronic acid. Also, polyurethanes, silicones,and polyesters could be used and other polymers could also be used ifthey can be dissolved and cured or polymerized on the stent such aspolyolefins, polyisobutylene and ethylene-alphaolefin copolymers;acrylic polymers and copolymers, vinyl halide polymers and copolymers,such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methylether; polyvinylidene halides, such as polyvinylidene fluoride andpolyvinylidene chloride; polyacrylonitrile; polyvinyl ketones; polyvinylaromatics, such as polystyrene; polyvinyl esters, such as polyvinylacetate; copolymers of vinyl monomers with each other and olefins, suchas ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers;polyamides, such as Nylon 66 and polycaprolactam; alkyd resins;polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins;rayon; rayon-triacetate; cellulose, cellulose acetate, cellulosebutyrate; cellulose acetate butyrate; cellophane; cellulose nitrate;cellulose propionate; cellulose ethers; and carboxymethyl cellulose.

Ethylene vinyl alcohol is functionally a very suitable choice ofpolymer. Ethylene vinyl alcohol copolymer, commonly known by the genericname EVOH or by the trade name EVOH, refers to copolymers comprisingresidues of both ethylene and vinyl alcohol monomers. One of ordinaryskill in the art understands that ethylene vinyl alcohol copolymer mayalso be a terpolymer so as to include small amounts of additionalmonomers, for example less than about five (5) mole percentage ofstyrenes, propylene, or other suitable monomers. In a useful embodiment,the copolymer comprises a mole percent of ethylene of from about 27% toabout 47%. Typically, 44 mole percent ethylene is suitable. Ethylenevinyl alcohol copolymers are available commercially from companies suchas Aldrich Chemical Company, Milwaukee, Wis., or EVOH Company ofAmerica, Lisle, Ill., or can be prepared by conventional polymerizationprocedures that are well known to one of ordinary skill in the art. Thecopolymer possesses good adhesive qualities to the surface of a stent,particularly stainless steel surfaces, and has illustrated the abilityto expand with a stent without any significant detachment of thecopolymer from the surface of the stent.

The solvent should be mutually compatible with the polymer and should becapable of placing the polymer into solution at the concentrationdesired in the solution. Useful solvents should also be able to expandthe chains of the polymer for maximum interaction with the surface ofthe device, such as a metallic surface of a stent. Examples of solventcan include, but are not limited to, dimethylsulfoxide (DMSO),chloroform, acetone, water (buffered saline), xylene, acetone, methanol,ethanol, 1-propanol, tetrahydrofuran, 1-butanone, dimethylformamide,dimethylacetamide, cyclohexanone, ethyl acetate, methylethylketone,propylene glycol monomethylether, isopropanol, N-methyl pyrrolidinone,toluene and mixtures thereof.

By way of example, and not limitation, the polymer can comprise fromabout 0.1% to about 35%, more narrowly about 2% to about 20% by weightof the total weight of the composition, and the solvent can comprisefrom about 65% to about 99.9%, more narrowly about 80% to about 98% byweight of the total weight of the composition. A specific weight ratiois dependent on factors such as the material from which the implantabledevice is made and the geometrical structure of the device.

In accordance with another embodiment, a fluid can be added to thecomposition to enhance the wetting of the composition for a more uniformcoating application. To enhance the wetting of the composition, asuitable fluid typically has a high capillary permeation. Capillarypermeation or wetting is the movement of a fluid on a solid substratedriven by interfacial energetics. Capillary permeation is quantitated bya contact angle, defined as an angle at the tangent of a droplet in afluid phase that has taken an equilibrium shape on a solid surface. Alow contact angle means a higher wetting liquid. A suitably highcapillary permeation corresponds to a contact angle less than about 90°.FIG. 1A illustrates a fluid droplet 10A on a solid substrate 12, forexample a stainless steel surface. Fluid droplet 10A has a highcapillary permeation that corresponds to a contact angle Φ₁, which isless than about 90°. In contrast, FIG. 1B illustrates a fluid droplet10B on solid substrate 12, having a low capillary permeation thatcorresponds to a contact angle Φ₂, which is greater than about 90°. Thewetting fluid, typically, should have a viscosity not greater than about50 centipoise, narrowly about 0.3 to about 5 centipoise, more narrowlyabout 0.4 to about 2.5 centipoise. The wetting fluid, accordingly, whenadded to the composition, reduces the viscosity of composition.

The wetting fluid should be mutually compatible with the polymer and thesolvent and should not precipitate the polymer. The wetting fluid canalso act as the solvent. Useful examples of the wetting fluid include,but are not limited to, tetrahydrofuran (THF), dimethylformamide (DMF),1-butanol, n-butyl acetate, dimethyl acetamide (DMAC), and mixtures andcombinations thereof. By way of example and not limitation, the polymercan comprise from about 0.1% to about 35%, more narrowly from about 2%to about 20% by weight of the total weight of the composition; thesolvent can comprise from about 19.9% to about 98.9%, more narrowly fromabout 58% to about 84% by weight of the total weight of the composition;the wetting fluid can comprise from about 1% to about 80%, more narrowlyfrom about 5% to about 40% by weight of the total weight of thecomposition. The specific weight ratio of the wetting fluid depends onthe type of wetting fluid employed and type of and the weight ratio ofthe polymer and the solvent. More particularly, tetrahydrofuran used asthe wetting fluid can comprise, for example, from about 1% to about 44%,more narrowly about 21% by weight of the total weight of the solution.Dimethylformamide used as the wetting fluid can comprise, for example,from about 1% to about 80%, more narrowly about 8% by weight of thetotal weight of the solution. 1-butanol used as the wetting fluid cancomprise, for example, from about 1% to about 33%, more narrowly about9% by weight of the total weight of the solution. N-butyl acetate usedas the wetting fluid can comprise, for example, from about 1% to about34%, more narrowly about 14% by weight of the total weight of thesolution. Dimethyl acetamide used as the wetting fluid can comprise, forexample, from about 1% to about 40%, more narrowly about 20% by weightof the total weight of the solution.

The presence of an active ingredient in a polymeric matrix typicallyinterferes with the ability of the matrix to adhere effectively to thesurface of the device. An increase in the quantity of the activeingredient reduces the effectiveness of the adhesion. High drug loadingsof, for example, 10-40% by weight in the coating significantly hinderthe retention of the coating on the surface of the device. The primerlayer serves as a functionally useful intermediary layer between thesurface of the device and an active ingredient-containing or reservoircoating. The primer layer provides for an adhesive tie between thereservoir coating and the device—which, in effect, would also allow forthe quantity of the active ingredient in the reservoir coating to beincreased without compromising the ability of the reservoir coating tobe effectively contained on the device during delivery and, ifapplicable, expansion of the device. Ethylene vinyl alcohol copolymeradheres well to metallic surfaces, particularly devices made fromstainless steel. The copolymer has illustrated good elastic qualities,which allow the copolymer to be delivered and, if applicable, expandedwith the device without any significant detachment of the copolymer formthe surface of the device.

Table 1 illustrates some examples of suitable combinations for theprimer composition:

TABLE 1 Wetting Polymer Solvent Fluid Initiators EVOH DMSO — — EVOH DMSOTHF — polyester polyurethanes dimethylformamide — — polyesterpolyurethanes dimethylformamide DMAC — polycaprolactone chloroformn-butyl acetate polyacrylate polyurethane ethyl acetate — benzophenonepolyacrylated polyurethane ethyl acetate — 1-hydroxycyclohexyl phenylketone polyethyleneamine H₂O — — methacrylic acid THF — — copolymerethylene vinylacetate methylethylketone — — (e.g., 40% vinyl acetatecontent) aminopropyltriethoxysilane ethanol/water — — 95/5 blend (w/w)(3-glydidoxypropyl) toluene — — methyldiethoxysilane tetra-iso-propyltitanate isopropanol — — (e.g., 0.25% w/w in isopropanol) tetra-n-butyltitanate ethyl acetate — — (e.g., 0.1-5% w/w in ethyl acetate)

Composition for Forming the Active Ingredient Layer

The embodiments of the composition for an active ingredient-containingor reservoir layer are prepared by conventional methods wherein allcomponents are combined, then blended. More particularly, in accordanceto one embodiment, a predetermined amount of a polymeric compound isadded to a predetermined amount of a mutually compatible solvent orcombination of solvents. The polymeric compound can be added at ambientpressure and under anhydrous atmosphere. If necessary, gentle heatingand stirring and/or mixing can be employed to effect dissolution of thepolymer into the solvent, for example 12 hours in a water bath at about60° C.

The polymer chosen must be a polymer that is biocompatible and minimizesirritation to the vessel wall when the device is implanted. The polymermay be either a biostable or a bioabsorbable polymer. Bioabsorbablepolymers that could be used include poly(hydroxyvalerate), poly(L-lacticacid), polycaprolactone, poly(lactide-co-glycolide),poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone,polyorthoesters, polyanhydrides, poly(glycolic acid), poly(D,L-lacticacid), poly(glycolic acid-co-trimethylene carbonate), polyphosphoesters,polyphosphoester urethanes, poly(amino acids), cyanoacrylates,poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters)(e.g. PEO/PLA), polyalkylene oxalates, polyphosphazenes and biomoleculessuch as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronicacid. Also, biostable polymers with a relatively low chronic tissueresponse such as polyurethanes, silicones, and polyesters could be usedand other polymers could also be used if they can be dissolved and curedor polymerized on the stent such as polyolefins, polyisobutylene andethylene-alphaolefin copolymers; acrylic polymers and copolymers, vinylhalide polymers and copolymers, such as polyvinyl chloride; polyvinylethers, such as polyvinyl methyl ether; polyvinylidene halides, such aspolyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile;polyvinyl ketones; polyvinyl aromatics, such as polystyrene; polyvinylesters, such as polyvinyl acetate; copolymers of vinyl monomers witheach other and olefins, such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers; polyamides, such as Nylon 66 and polycaprolactam; alkydresins; polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxyresins; rayon; rayon-triacetate; cellulose, cellulose acetate, cellulosebutyrate; cellulose acetate butyrate; cellophane; cellulose nitrate;cellulose propionate; cellulose ethers; and carboxymethyl cellulose.

Ethylene vinyl alcohol is functionally a very suitable choice ofpolymer. The copolymer allows for good control capabilities over therelease rate of the active ingredient. As a general rule, an increase inthe amount of the ethylene comonomer content decreases the rate that theactive ingredient is released from the copolymer matrix. The releaserate of the active ingredient typically decreases as the hydrophilicityof the copolymer decreases. An increase in the amount of the ethylenecomonomer content increases the overall hydrophobicity of the copolymer,especially as the content of vinyl alcohol is concomitantly reduced. Itis also known that the release rate and the cumulative amount of theactive ingredient that is released is directly proportional to the totalinitial content of the ingredient in the copolymer matrix. Accordingly,a wide spectrum of release rates can be achieved by modifying theethylene comonomer content and the initial amount of the activeingredient.

The choice of polymer for the reservoir layer can be the same as ordifferent from the selected polymer for the primer layer. The use of thesame polymer significantly reduces or eliminates any interfacialincompatibilities, such as lack of an adhesive tie or bond, which mayexist with the employment of two different polymeric layers. In effect,it can be said that the use of the same polymeric material for theprimer layer and the reservoir layer results in the formation of asingle-layered coating.

The solvent should be capable of placing the polymer into solution atthe concentration desired in the solution. Examples of solvent caninclude, but are not limited to, DMSO, chloroform, acetone, water(buffered saline), xylene, acetone, methanol, ethanol, 1-propanol,tetrahydrofuran, 1-butanone, dimethylformamide, dimethylacetamide,cyclohexanone, and N-methylpyrrolidinone. With the use of low ethylenecontent, e.g., 29 mol %, ethylene vinyl alcohol copolymer, a suitablechoice of solvent is iso-propylalcohol (IPA) admixed with water.

Sufficient amounts of an active ingredient are dispersed in the blendedcomposition of the polymer and the solvent. The active ingredient shouldbe in true solution or saturated in the blended composition. If theactive ingredient is not completely soluble in the composition,operations including mixing, stirring, and/or agitation can be employedto effect homogeneity of the residues. The active ingredient may beadded so that the dispersion is in fine particles. The mixing of theactive ingredient can be conducted in an anhydrous atmosphere, atambient pressure, and at room temperature such that supersaturating theactive ingredient is not desired.

The active ingredient should inhibit the activity of vascular smoothmuscle cells. More specifically, the active ingredient is aimed atinhibiting abnormal or inappropriate migration and/or proliferation ofsmooth muscle cells.

“Smooth muscle cells” include those cells derived from the medial andadventitial layers of the vessel which proliferate in intimalhyperplastic vascular sites following vascular trauma or injury. Underlight microscopic examination, characteristics of smooth muscle cellsinclude a histological morphology of a spindle shape with an oblongnucleus located centrally in the cell with nucleoli present andmyofibrils in the sarcoplasm. Under electron microscopic examination,smooth muscle cells have long slender mitochondria in the juxtanuclearsarcoplasm, a few tubular elements of granular endoplasmic reticulum,and numerous clusters of free ribosomes. A small Golgi complex may alsobe located near one pole of the nucleus.

“Migration” of smooth muscle cells means movement of these cells in vivofrom the medial layers of a vessel into the intima, such as may also bestudied in vitro by following the motion of a cell from one location toanother, e.g., using time-lapse cinematography or a video recorder andmanual counting of smooth muscle cell migration out of a defined area inthe tissue culture over time.

“Proliferation” of smooth muscle cells means increase in cell number.

“Abnormal” or “inappropriate” proliferation means division, growth ormigration of cells occurring more rapidly or to a significantly greaterextent than typically occurs in a normally functioning cell of the sametype, i.e., hyper-proliferation.

“Inhibiting” cellular activity means reducing, delaying or eliminatingsmooth muscle cell hyperplasia, restenosis, and vascular occlusions,particularly following biologically or mechanically mediated vascularinjury or trauma or under conditions that would predispose a mammal tosuffer such a vascular injury or trauma. As used herein, the term“reducing” means decreasing the intimal thickening that results fromstimulation of smooth muscle cell proliferation. “Delaying” meansretarding the progression of the hyper-proliferative vascular disease ordelaying the time until onset of visible intimal hyperplasia, asobserved, for example, by histological or angiographic examination.“Elimination” of restenosis following vascular trauma or injury meanscompletely “reducing” and/or completely “delaying” intimal hyperplasiain a patient to an extent which makes it no longer necessary tosurgically intervene, i.e., to re-establish a suitable blood flowthrough the vessel by, for example, repeat angioplasty, atherectomy, orcoronary artery bypass surgery. The effects of reducing, delaying, oreliminating restenosis may be determined by methods known to one ofordinary skill in the art, including, but not limited to, angiography,intravascular ultrasound, fluoroscopic imaging, fiber opticvisualization, optical coherence tomography, intravascular MRI, orbiopsy and histology. Biologically mediated vascular injury includes,but is not limited to, injury caused by or attributed to autoimmunedisorders, alloimmune related disorders, infectious disorders includingendotoxins and herpes viruses such as cytomegalovirus, metabolicdisorders such as atherosclerosis, and vascular injury resulting fromhypothermia and irradiation. Mechanically mediated vascular injuryincludes, but is not limited to, vascular injury caused bycatheterization procedures or vascular scraping procedures such aspercutaneous transluminal coronary angioplasty, vascular surgery, stentplacement, transplantation surgery, laser treatment, and other invasiveprocedures which disrupted the integrity of the vascular intima orendothelium. The active ingredient of the invention is not restricted inuse for therapy following vascular injury or trauma; rather, theusefulness of the active ingredient will also be determined by theingredient's ability to inhibit cellular activity of smooth muscle cellsor inhibit the development of restenosis.

The active ingredient also includes any substance capable of exerting atherapeutic or prophylactic effect in the practice of the presentinvention as well as having positive pharmacological effects on theexpression of the extracellular matrix. The active ingredient can alsobe for enhancing wound healing in a vascular site and improving thestructural and elastic properties of the vascular site. Examples of suchactive ingredients include antiproliferative substances as well asantineoplastic, antiinflammatory, antiplatelet, anticoagulant,antifibrin, antithrombin, antimitotic, antibiotic, antioxidant, andcombinations thereof. A suitable example of an antiproliferativesubstance includes actinomycin D, or derivatives and analogs thereof(manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee,Wis. 53233; or COSMEGEN available from Merck). Synonyms of actinomycin Dinclude dactinomycin, actinomycin IV, actinomycin I₁, actinomycin X₁,and actinomycin C₁. Examples of suitable antineoplastics includepaclitaxel and docetaxel. Examples of suitable antiplatelets,anticoagulants, antifibrins, and antithrombins include sodium heparin,low molecular weight heparin, hirudin, argatroban, forskolin, vapiprost,prostacyclin and prostacyclin analogs, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist, recombinanthirudin, thrombin inhibitor (available from Biogen), and 7E-3B® (anantiplatelet drug from Centocore). Examples of suitable antimitoticagents include methotrexate, azathioprine, vincristine, vinblastine,fluorouracil, adriamycin, and mutamycin. Examples of suitable cytostaticor antiproliferative agents include angiopeptin (a somatostatin analogfrom Ibsen), angiotensin converting enzyme inhibitors such as CAPTOPRIL(available from Squibb), CILAZAPRIL (available from Hoffman-LaRoche), orLISINOPRIL (available from Merck); calcium channel blockers (such asNifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonist, LOVASTATIN (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug from Merck),monoclonal antibodies (such as PDGF receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitor (available formGlazo), Seramin (a PDGF antagonist), serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. Other therapeutic substances or agents which may beappropriate include alpha-interferon, genetically engineered epithelialcells, and dexamethasone. Exposure of the composition to the activeingredient is not permitted to adversely alter the active ingredient'scomposition or characteristic. Accordingly, the particular activeingredient is selected for mutual compatibility with the blendedcomposition.

The dosage or concentration of the active ingredient required to producea favorable therapeutic effect should be less than the level at whichthe active ingredient produces toxic effects and greater than the levelat which non-therapeutic results are obtained. The dosage orconcentration of the active ingredient required to inhibit the desiredcellular activity of the vascular region can depend upon factors such asthe particular circumstances of the patient; the nature of the trauma;the nature of the therapy desired; the time over which the ingredientadministered resides at the vascular site; and if other bioactivesubstances are employed, the nature and type of the substance orcombination of substances. Therapeutic effective dosages can bedetermined empirically, for example by infusing vessels from suitableanimal model systems and using immunohistochemical, fluorescent orelectron microscopy methods to detect the agent and its effects, or byconducting suitable in vitro studies. Standard pharmacological testprocedures to determine dosages are understood by one of ordinary skillin the art.

By way of example, the polymer can comprise from about 0.1% to about35%, more narrowly from about 2% to about 20% by weight of the totalweight of the composition, the solvent can comprise from about 59.9% toabout 99.8%, more narrowly from about 79% to about 87% by weight of thetotal weight of the composition, and the active ingredient can comprisefrom about 0.1% to about 40%, more narrowly from about 1% to about 9% byweight of the total weight of the composition. More than 9% by weight ofthe active ingredient could adversely affect characteristics that aredesirable in the polymeric coating, such as adhesion of the coating tothe device. With the use of the primer layer, weight ratios of more than9% for the active ingredient are achievable. Selection of a specificweight ratio of the polymer and solvent is dependent on factors such as,but not limited to, the material from which the device is made, thegeometrical structure of the device, and the type and amount of theactive ingredient employed. The particular weight percentage of theactive ingredient mixed within the composition depends on factors suchas duration of the release, cumulative amount of release, and releaserate that is desired.

Optionally, a second fluid or solvent, such as tetrahydrofuran (THF) ordimethylformamide (DMF) can be used to improve the solubility of anactive ingredient in the composition and/or to increase the wetting ofthe composition. Increasing the wetting of the composition has beendiscovered to lead to the application of a more uniformed coating. Thesecond fluid or solvent can be added to the composition or the activeingredient can be added to the second solvent prior to admixture withthe blend.

In this embodiment with a second fluid, by way of example, the polymercan comprise from about 0.1% to about 35%, more narrowly from about 2%to about 20% by weight of the total weight of the composition, thesolvent can comprise from about 19.8% to about 98.8%, more narrowly fromabout 49% to about 79% by weight of the total weight of the composition,the second solvent can comprise from about 1% to about 80%, morenarrowly from about 5% to about 40% by weight of the total weight of thecomposition, and the active ingredient can comprise from about 0.1% toabout 40%, more narrowly from about 1% to about 9% by weight of thetotal weight of the composition. Selection of a specific weight ratio ofthe polymer, the solvent, and the second solvent is dependent on factorssuch as, but not limited to, the material from which the implantabledevice is made, the geometrical structure of the device, and the typeand amount of the active ingredient employed. The particular weightpercentage of the active ingredient mixed within the composition dependson factors such as duration of the release, cumulative amount ofrelease, and release rate that is desired.

Table 2 is an exemplary list of suitable combinations in accordance withvarious embodiment of the present invention:

TABLE 2 SECOND ACTIVE POLYMER SOLVENT SOLVENT INGREDIENT EVOH (29 mol %IPA/H₂O — Actinomycin D ethylene content e.g., (1:1) Soarnol ®) EVOH (44mol % DMSO THF Actinomycin D ethylene content) EVOH DMSO THF ActinomycinD EVOH DMSO DMF Paclitaxel poly(L-lactic acid) chloroform —dexamethasone poly(lactic acid-co- acetone — dexamethasone glycolicacid) Polyether urethane N-methyl — tocopherol pyrrolidinone

Composition for Forming the Rate Reducing Membrane

The embodiments of the composition for a rate-reducing membrane ordiffusion barrier layer are prepared by conventional methods wherein allcomponents are combined. In the embodiment with the use of particles,dispersion techniques should also be employed to circumventagglomeration or formation of particle flocs.

More particularly, in accordance with one embodiment, the embodimentsfor the composition for the reservoir layer can be applied on a selectedregion of the reservoir layer to form a rate reducing member or abarrier layer. The barrier layer can reduce the rate of release or delaythe time at which the active ingredient is released from the reservoirlayer. In one embodiment, for maximum blood compatibility, polyethyleneglycol or polyethylene oxide can also be added to the blend. Ethylenevinyl alcohol is functionally a very suitable choice of polymer. Thecopolymer allows for good control capabilities over the release rate ofthe active ingredient. As a general rule, an increase in the amount ofthe ethylene comonomer content decreases the rate that the activeingredient is released from the copolymer matrix. The release rate ofthe active ingredient decreases as the hydrophilicity of the polymerdecreases. An increase in the amount of the ethylene comonomer contentincreases the overall hydrophobicity of the copolymer, especially as thecontent of vinyl alcohol is concomitantly reduced.

Usefully, the choice of polymer for the barrier layer can be the same asthe selected polymer for the reservoir. The use of the same polymer, asdescribed for some of the embodiments, significantly reduces oreliminates any interfacial incompatibilities, such as lack of adhesion,which may exist in the employment of two different polymeric layers. Ineffect, it can be said that the use, if desired, of the same polymericmaterial for the barrier layer and the reservoir layer results in theformation of a single-layered coating. In other words, the use of thesame polymeric material results in a seamless multi-layered coating inwhich the layers vary in terms of their content. Defined interfacialboundaries are, accordingly, significantly reduced or eliminated.

In accordance with another embodiment, particles of inorganic or organictype are added to the blend. The particles should be dispersed in theblend. Dispersed is defined as the particles being present as individualparticles, not agglomerates or flocs. In certain polymer-solvent blends,certain particles will disperse with ordinary mixing. Otherwise theparticles can be dispersed in the composition by high shear processessuch as ball mill, disc mill, sand mill, attritor, rotor stator mixer,ultrasonication—all such high shear dispersion techniques being wellknown to one of ordinary skill in the art. Optionally, one of theaforementioned wetting fluids can also be added to the blend. Thewetting fluid can be added prior to, contemporaneously with, orsubsequent to the agitation. Biocompatible dispersing agents in the formof surfactants, emulsifiers, or stablilizers may also be added to theblend to assist in particle dispersion.

The particles can be made from any suitable material having barrier-typeproperties, such as, but not limited to tortuousity, excluded volume,and adsorptivity. Tortuosity refers to the exclusion of space in thepolymer matrix for the creation of a defined space or a tortuous paththrough and about which the active ingredient must travel to be expelledfrom the layer. Excluded volume refers to the volume displaced by theparticles that would otherwise be available for the diffusion of theactive ingredient. Adsorptivity refers to the chromatographic effectwhich is dependent upon the interaction between the active ingredientused in combination with the particle. The active ingredient may bepartially adsorbed and released by the surface of the particles, such assilica or fumed carbon particles.

In one embodiment, the particles can be made from a metal oxide, such asrutile titanium oxide, anatase titanium dioxide, niobium oxide, tantalumoxide, zirconium oxide, iridium oxide, or tungsten oxide. In anotherembodiment, the particles can be made from a main group oxide such assilica (silicon oxide) or alumina (aluminum oxide). Metallic particlessuch as gold, hafnium, platinum, iridium, palladium, tungsten, tantalum,niobium, zirconium, titanium, aluminum, or chromium can also beemployed. In another embodiment, carbonaceous particles made from, forexample, lamp black, furnace black, carbon black, fumed carbon black,gas black, channel black, activated charcoal, diamond, diamond likecarbon, or CVD diamond can be employed. In yet another embodiment, theparticles can be made from nitrides such as titanium nitride, chromiumnitride, and zirconium nitride. In yet another embodiment, carbides suchas tungsten carbide, silicon carbide, or titanium carbide, and calciumsalts such as hydroxyapatite, dahlite, brushite, tricalcium phosphate,calcium sulphate, and calcium carbonate can be used. Other inorganicparticles can include particles made from silicides, barium titanate,and strontium titanate.

In yet another embodiment, the particles can be made from a suitablepolymer including polymers of polyolefins, polyurethanes, cellulosics(i.e., polymers having mer units derived from cellulose), polyesters,polyamides, poly(hexamethylene isophthalamide/terephthalamide)(commercially available as SELAR PA™), poly(ethyleneterephthalate-co-p-oxybenzoate) (PET/PHB, e.g., copolymer having about60-80 mole percent PHB), poly(hydroxy amide ethers), polyacrylates,polyacrylonitrile, acrylonitrile/styrene copolymer (commerciallyavailable as LOPAC), rubber-modified acrylonitrile/acrylate copolymer(commercially available as BAREX), poly(methyl methacrylate), liquidcrystal polymers (LCP) (e.g., VECTRA available from Hoescht-Celanese,ZENITE available from DuPont, and XYDAR available from Amoco PerformanceChemicals), poly(phenylene sulfide), polystyrenes, polycarbonates,poly(vinyl alcohols), poly(ethylene-vinyl alcohol) (EVOH, e.g., havingabout 27 to about 47 mole percent of ethylene content), epoxies composedof bisphenol A based diepoxides with amine cure, aliphatic polyketones(e.g., CARILON available from Shell, and KETONEX available from BritishPetroleum), polysulfones, poly(ester-sulfone), polyurethane-sulfone),poly(carbonate-sulfone), poly(3-hydroxyoxetane), poly(amino ethers),gelatin, amylose, parylene-C, parylene-D, parylene-N.

Representatives polyolefins include those based upon alpha-monoolefinmonomers having from about 2 to 6 carbon atoms and halogen substitutedolefins, i.e., halogenated polyolefins. By way of example, and notlimitation, low to high density polyethylenes, essentially unplasticizedpoly (vinyl chloride), poly (vinylidene chloride), poly (vinylfluoride), poly (vinylidene fluoride), poly (tetrafluoroethylene)(Teflon), poly (chlorotrifluoroethylene) (KEL-F), and mixtures thereofare suitable. Low to high density polyethylenes are generally understoodto have densities of about 0.92 g cm⁻³ to about 0.96 g cm⁻³, however, nobright line can be drawn for density classifications and the density canvary according to the supplier.

Representative polyurethanes include polyurethanes having a glasstransition temperature above a storage or ambient temperature, forexample having a glass transition temperature of at least 40° C. to 60°C., or having a non-polar soft segment which includes a hydrocarbon,silicone, fluorosilicone, or mixtures thereof. For example, ELAST-EON,manufactured by Elastomedic/CSIRO Molecular Science, is a polyurethanewith a non-polar soft segment which is made from 1,4-butanediol,4,4′-methylenediphenyl diisocyanate, and a soft segment composed of ablend poly(hexamethylene oxide) (PHMO) andbishydroxyethoxypropylpolydimethylsiloxane (PDMS). A useful example hasa blend of 20% by weight PHMO and 80% by weight PDMS.

Representative examples of cellulosics include, but are not limited to,cellulose acetate having a degree of substitution (DS) greater thanabout 0.8 or less than about 0.6, ethyl cellulose, cellulose nitrate,cellulose acetate butyrate, methyl cellulose, and mixtures thereof.

Representative polyesters include saturated or unsaturated polyesterssuch as, but not limited to, poly (butylene terephthalate),poly(ethylene 2,6-naphthalene dicarboxylate) (PEN), and poly (ethyleneterephthalate).

Representative polyamides include crystalline or amorphous polyamidessuch as, but not limited to, nylon-6, nylon-6,6, nylon-6,9, nylon-6,10,aromatic nylon MXD6 (manufactured by Mitsubishi Gas Chemical AmericaInc.), and mixtures thereof.

Representative polyacrylates include, but are not limited to,poly(methylmethacrylate) and polymethacrylate.

In one embodiment, the particle can be a mixture of the aforementionedpolymers. For example, the polymer can comprise about 70% to about 99%by weight acrylonitrile and about 30% to about 1% by weight styrene.Similarly, copolymers of vinyl chloride and vinylidene chloride with avinyl chloride content of about 1 to about 30 mole percent and PET/PHBcopolymers with a PHB content of about 60 to about 80 mole percentfunction effectively.

Examples of the Device

The device or prosthesis used in conjunction with the above-describedcompositions may be any suitable device used for the release of anactive ingredient, examples of which include self-expandable stents,balloon-expandable stents, and stent-grafts, and grafts. The underlyingstructure of the device can be virtually any design. The device can bemade of a metallic material or an alloy such as, but not limited to,cobalt chromium alloy (ELGILOY), stainless steel (316L), “MP35N,”“MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention. A polymeric device should becompatible with the selected compositions. The ethylene vinyl alcoholcopolymer, however, adheres very well to metallic materials, morespecifically to stainless steel.

Methods For Applying the Compositions to the Device

To form the primer layer, the surface of the device or prosthesis shouldbe clean and free from contaminants that may be introduced duringmanufacturing. However, the surface of the prosthesis requires noparticular surface treatment to retain the applied coating. Metallicsurfaces of stents can be, for example, cleaned by argon plasma processas is well known to one of ordinary skill in the art. Application of thecomposition can be by any conventional method, such as by spraying thecomposition onto the prosthesis or immersing the prosthesis in thecomposition. Operations such as wiping, centrifugation, blowing, orother web clearing acts can also be performed to achieve a more uniformcoating. Briefly, wiping refers to physical removal of excess coatingfrom the surface of the stent; centrifugation refers to rapid rotationof the stent about an axis of rotation; and blowing refers toapplication of air at a selected pressure to the deposited coating. Theexcess coating can also be vacuumed off the surface of the device. Theaddition of a wetting fluid leads to a consistent application of thecomposition, which also causes the coating to be uniformly deposited onthe surface of the prosthesis.

With the use of the thermoplastic polymers, such as ethylene vinylalcohol copolymer, polycaprolactone, poly(lactide-co-glycolide),poly(hydroxybutyrate), etc., the deposited primer composition should beexposed to a heat treatment at temperature range greater than about theglass transition temperature (T_(g)) and less than about the meltingtemperature (T_(m)) of the selected polymer. Unexpected results havebeen discovered with treatment of the composition under this temperaturerange, specifically strong adhesion or bonding of the coating to themetallic surface of a stent. The device should be exposed to the heattreatment for any suitable duration of time, which would allow for theformation of the primer coating on the surface of the device and allowsfor the evaporation of the solvent or combination of solvent and wettingfluid. It is understood that essentially all of the solvent and thewetting fluid will be removed from the composition but traces orresidues can remain blended with the polymer.

Table 3 lists the T_(g) and T_(m), for some of the polymers used in theembodiments of the present invention. T_(g) and T_(m) of polymers areattainable by one or ordinary skill in the art. The cited exemplarytemperature and time for exposure is provided by way of illustration andit is not meant to be limiting.

TABLE 3 Exemplary Exemplary Duration of T_(g) T_(m) Temperature Time ForPolymer (° C.) (° C.) (° C.) Heating EVOH 55 165 140 4 hourspolycaprolactone −60 60 50 2 hours ethylene vinyl 36 63 45 2 hoursacetate (e.g., 33% vinyl- acetate content) Polyvinyl 75-85* 200-220* 1652 hours alcohol *Exact temperature depends on the degree of hydrolysiswhich is also known as the amount of residual acetate.

With the use of one of the aforementioned thermoset polymers, the use ofinitiators may be required. By way of example, epoxy systems consistingof diglycidyl ether of bisphenol A resins can be cured with aminecuratives, thermoset polyurethane prepolymers can be cured with polyols,polyamines, or water (moisture), and acrylated urethane can be curedwith UV light. Examples 27 and 28 provide illustrative descriptions. Ifbaked, the temperature can be above the T_(g) of the selected polymer.

With the use of the inorganic polymers, such as silanes, titanates, andzirconates the composition containing the prepolymer or precursor isapplied and the solvent is allowed to evaporate. Example 29 provides abrief description.

Subsequent to the formation of the primer layer, the compositioncontaining the active ingredient can be applied to a designated regionof the primer coating. Masking techniques can be implemented forapplying compositions containing different active ingredients toselected regions of the primer layer. Accordingly, stents having variouscocktail formulations or combinations of a variety of active ingredientscan be manufactured. The solvent(s) or the combination of the solvent(s)and the wetting fluid is removed from the composition by allowing thesolvent(s) or combination of the solvent(s) and the wetting fluid toevaporate. The evaporation can be induced by heating device at apredetermined temperature for a predetermined period of time. Forexample, the device can be heated at a temperature of about 60° C. forabout 12 hours to about 24 hours. The heating can be conducted in ananhydrous atmosphere and at ambient pressure and should not exceed thetemperature which would adversely affect the active ingredient. Theheating can, alternatively, be conducted under a vacuum condition. It isunderstood that essentially all of the solvent and the wetting fluidwill be removed from the compositision but traces or residues can remainblended with the polymer.

The diffusion barrier layer can be deposited on a designated region ofthe active ingredient-containing coating subsequent to the evaporationof the solvent(s) or solvent(s)/wetting fluid and the drying of thepolymer for the active ingredient-containing coating. The diffusionbarrier layer can also be applied by spraying the composition onto thedevice or immersing the device in the composition. The above-describedprocesses can be similarly repeated for the formation of the diffusionbarrier layer.

Coating

Some of the various embodiments of the present invention are illustratedby FIGS. 2A-2E, 3A and 3B. The Figures have not been drawn to scale, andthe depth and thickness of the various regions and layers have been overor under emphasized for illustrative purposes.

Referring to FIG. 2A, a body of a stent 20 is illustrated having asurface 22, e.g., metallic surface such as stainless steel. A coating 24is disposed on surface 22. Coating 24 includes a first region 26defining the reservoir portion of coating 24 containing the activeingredient. A second region 28, free from any active ingredients,defines the primer portion of coating 24. In accordance with anotherembodiment, as illustrated in FIG. 2B, coating 24 can include a thirdregion 30 defining a barrier portion, free from any particles. Thirdregion 30, as illustrated in FIG. 2C, can also include particles 32.

Coating 24 for FIGS. 2A-2C is made from only one of the aforementionedpolymeric materials, e.g., EVOH, and accordingly, the existence of anyinterfacial boundaries between the first 26, second 28, and third 30regions is essentially reduced or eliminated. Elimination of interfacialboundaries essentially reduces or eliminates any incompatibilities, suchas adhesiveness, that may exist when using layers of different polymericmaterials.

By way of example, and not limitation, reservoir region 26 for coating24 can have a thickness T₁ of about 0.5 microns to about 10 microns. Theparticular thickness T₁ is based on the type of procedure for whichstent 20 is employed and the amount of the active ingredient that isdesired to be delivered. Primer region 28 can have any suitablethickness T₂, examples of which can be in the range of about 0.1 toabout 10 microns, more narrowly about 0.1 to about 2 microns. Diffusionbarrier region 30 can have any suitable thickness T₃, as the thicknessT₃ is dependent on parameters such as, but not limited to, the desiredrate or duration of release and the procedure for which stent 20 will beused. Diffusion barrier region 30 can have a thickness T₃ of about 0.1to about 10 microns, more narrowly from about 0.25 to about 2 microns.If particles 32 are employed, for a smooth outer surface, the size ofparticles 32 should not be greater than about 10% of thickness T₃ ofdiffusion barrier region 30. Additionally, the particle volume fractionX_(p) should not exceed about 0.74. Packing density or particle volumefraction X_(p) can be defined by the following equation:

X _(p) =V _(particles)/(V _(particles) +V _(polymer))

wherein V is volume.

In yet another embodiment, as illustrated in FIG. 2D, reservoir region26 can include a first and second reservoir sections 26A and 26B, eachcontaining a different active ingredient, e.g., actinomycin D and taxol,respectively. Accordingly, coating 24 can carry a combination of atleast two different active ingredients for sustained delivery. First andsecond sections 26A and 26B can be deposited by, for example, maskingthe area of primer region 28 over second section 26B and applying afirst composition containing a first active ingredient to form firstsection 26A. First section 26A can then be masked and a secondcomposition containing a second active ingredient can be applied to formsecond section 26B. This procedure can be followed to from any suitablenumber of regions containing a different active ingredient.

In accordance with yet another embodiment, barrier region 30 can beformed on reservoir sections 26A and 26B, as illustrated in FIG. 2D.Referring to FIG. 2E, barrier region 30 can include a first barriersection 30A disposed over first reservoir section 26A containing a firstactive ingredient, e.g., actinomycin D. A second barrier section 30B isformed over second reservoir section 26B containing a second activeingredient, e.g., taxol. First barrier section 30A is particle free andsecond barrier section 30B contains particles 32. As a result, coating24 harbors two different release parameters for each of the activeingredients contained in reservoir sections 26A and 26B.

In accordance with yet another embodiment, different polymeric materialshaving interfacial compatibilities can be used to form individual,distinct layers for the primer, reservoir, and diffusion barriercomponents of the coating. Referring to FIG. 3A, a coating 34 isprovided having a primer layer 36, made from a first polymeric material,formed on surface 22 of stent 20. A reservoir layer 38 made from asecond polymeric material is deposited on a selected area of primerlayer 36. A barrier layer 40, made from a third polymeric material canbe deposited on reservoir layer 38.

One of ordinary skill in the art can appreciate that a variety ofcoating combinations can be provided with the practice of the presentinvention. For example, as illustrated in FIG. 3B, coating 34 containsprimer layer 36 made from a first polymeric material. Reservoir layer38, made from a second polymeric material, is formed on primer layer 36.Reservoir layer 38 contains first and second regions, illustrated as 38Aand 38B. First and second regions 38A and 38B each contain a differentactive ingredient. Barrier layer 40, made from a third polymericmaterial, can be deposited on reservoir layer 38. Barrier layer 40includes a first region 40A deposited over first region 38A of reservoirlayer 38. Barrier layer 40 additionally includes a second region 40Bdeposited over second region 38B of reservoir layer 38. Second region40B can include particles 32 and/or be made out of a fourth polymericmaterial to create a variety of different release parameters.

Examples of different polymeric materials having interfacialcompatibilities include, for example, an EVOH primer with a reservoirlayer of ethylene vinylacetate; a poly(n-butyl methacrylate) primer withan EVOH reservoir layer; an EVOH primer and a reservoir layer ofpolycaprolactone; and an epoxy primer consisting of the diglycidyletherof bisphenol A cured with polyamine curatives with an EVOH reservoirlayers. Other combinations can be derived by one of ordinary skill inthe art.

Method of Use

In accordance with the above-described method, the active ingredient canbe applied to a medical device, e.g., a stent, retained on the stentduring delivery and expansion of the stent, and released at a desiredcontrol rate and for a predetermined duration of time at the site ofimplantation. A stent having the above-described coating layers isuseful for a variety of medical procedures, including, by way ofexample, treatment of obstructions caused by tumors in bile ducts,esophagus, trachea/bronchi and other biological passageways. A stenthaving the above-described coating layers is particularly useful fortreating occluded regions of blood vessels caused abnormal orinappropriate migration and proliferation of smooth muscle cells,thrombosis, and restenosis. Stents may be placed in a wide array ofblood vessels, both arteries and veins. Representative examples of sitesinclude the iliac, renal, and coronary arteries. The application of thepresent invention should not, however, be limited to stents such thatthe embodiments of the coating can be used with a variety of medicalsubstrates.

Briefly, an angiogram is first performed to determine the appropriatepositioning for stent therapy. Angiography is typically accomplished byinjecting a radiopaque contrast agent through a catheter inserted intoan artery or vein as an x-ray is taken. A guidewire is then advancedthrough the lesion or proposed site of treatment. Over the guidewire ispassed a delivery catheter which allows a stent in its collapsedconfiguration to be inserted into the passageway. The delivery catheteris inserted either percutaneously or by surgery into the femoral artery,brachial artery, femoral vein, or brachial vein, and advanced into theappropriate blood vessel by steering the catheter through the vascularsystem under fluoroscopic guidance. A stent having the above describedcoating layers may then be expanded at the desired area of treatment. Apost insertion angiogram may also be utilized to confirm appropriatepositioning.

EXAMPLES

The embodiments of the invention will be illustrated by the followingset forth examples which are being given by way of illustration only andnot by way of limitation. All parameters and data are not be construedto unduly limit the scope of the embodiments of the invention.

Example 1

Multi-Link™ stents (available from Guidant Corporation) were cleaned byplacement in an ultrasonic bath of isopropyl alcohol solution for 10minutes. The stents were dried and plasma cleaned in a plasma chamber.An EVOH solution was made with 1 gram of EVOH and 7 grams of DMSO,making an EVOH:DMSO ratio of 1:7. The mixture was placed in a warm watershaker bath at 60° C. for 24 hours. The solution was cooled andvortexed. The cleaned Multi-Link™ stents were dipped in the EVOHsolution and then passed over a hot plate, for about 3-5 seconds, with atemperature setting of about 60° C. The coated stents were heated for 6hours in an air box and then placed in an oven at 60° C., under vacuumcondition, and for 24 hours. The coated stents were expanded on a 4.0 mmangioplasty balloon. The coatings remained intact on the stents. Thecoatings were transparent giving the Multi-Link™ stents a glossy-likeshine.

Example 2

Multi-Link™ stents were cleaned by placement in an ultrasonic bath ofisopropyl alcohol solution for 10 minutes. The stents were dried andplasma cleaned in a plasma chamber. An EVOH solution was made with 1gram of EVOH and 4 grams of DMSO, making an EVOH:DMSO ratio of 1:4.Dexamethasone was added to the 1:4 EVOH:DMSO solution. Dexamethasoneconstituted 9% by weight of the total weight of the solution. Thesolution was vortexed and placed in a tube. The cleaned Multi-Link™stents were attached to mandrel wires and dipped into the solution. Thecoated stents were passed over a hot plate, for about 3-5 seconds, witha temperature setting of about 60° C. The coated stents were cured for 6hours in an air box and then placed in a vacuum oven at 60° C. for 24hours. The above-recited step was repeated twice. The average weight ofthe coating was 0.0003 gram, having an estimated dexamethasone contentof 75 ug per stent. The coated stents were expanded on a 4.0 mmangioplasty balloon. The coatings remained intact on the stents.Verification of coverage and physical properties of the coatings werevisualized using a scanning electron microscope. The coatings weretransparent, giving the Multi-Link™ stents a glossy-like shine.

Example 3

Multi-Link Duet™ stents are cleaned by placement in an ultrasonic bathof isopropyl alcohol solution for 10 minutes. The stents are dried andplasma cleaned in a plasma chamber. The EVOH solution is made with 1gram of EVOH and 4 grams of DMSO, making an EVOH:DMSO ratio of 1:4.Dexamethasone is added to the 1:4 EVOH:DMSO solution. Dexamethasoneconstitutes 9% by weight of the total weight of the solution. Thesolution is vortexed and placed in a tube. The cleaned Multi-Link™stents are attached to mandrel wires and dipped into the solution. Thecoated stents are passed over a hot plate, for about 3-5 seconds, with atemperature setting of about 60° C. The coated stents are cured for 6hours in an air box then placed in a vacuum oven at 60° C. for 24 hours.The single layered dexamethasone/EVOH coated stents are dipped into the1:4 ratio EVOH:DMSO solution, free from dexamethasone. The stents arepassed over the hot plate, cured, and placed in the oven as previouslydescribed. The top coating will provide a barrier layer for controllingthe release of dexamethasone from the drug coated layer. The coatedstents can be expanded on a 4.0 mm angioplasty balloon. It is predictedthat the coatings will remain intact on the stents. The coatings will betransparent, giving the Multi-Link™ stents a glossy-like shine.

Example 4

Multi-Link™ stents were cleaned by placement in an ultrasonic bath ofisopropyl alcohol solution for 10 minutes. The stents were dried andplasma cleaned in a plasma chamber. An EVOH solution was made with 1gram of EVOH and 7 grams of DMSO, making an EVOH:DMSO ratio of 1:7.Vinblastine was added to the 1:7 EVOH:DMSO solution. Vinblastineconstituted 2.5% by weight of the total weight of the solution. Thesolution was vortexed and placed in a tube. The cleaned Multi-Link™stents were attached to mandrel wires and dipped into the solution. Thecoated stents were passed over a hot plate, for about 3-5 seconds, witha temperature setting of about 60° C. The coated stents were cured for 6hours in an air box then placed in a vacuum oven at 60° C. for 24 hours.The above process was repeated twice, having a total of three layers.The average weight of the coating was 0.00005 gram, with an estimatedvinblastine concentration of 12 microgram per stent. Some of the stentswere sterilized by electron beam radiation. The sterilized andunsterilized vinblastine coated stents were tested for a 24 hour elutionperiod by placing one sterilized and one unsterilized stent in 5 ml ofphosphated saline solution (pH 7.4) at room temperature with rotationalmotion. The amount of vinblastine eluted was evaluated by HighPerformance Liquid Chromatography (HPLC) analysis. The results of thistest are given below and plotted in FIG. 4. The data indicates thatelectron beam radiation procedure does not interfere in the release ofvinblastine from EVOH.

Release Profile For Vinblastine -- Unsterilized Time microgram Totalmicrogram microgram Release (Hours) Released Released per Hour 0 0 0 00.5 2.12 2.12 4.24 3 1.91 4.03 0.76 4 0.27 4.30 0.27 6 0.38 4.68 0.19 241.7 6.38 0.09

Release Profile For Vinblastine -- Sterilized Time Total uG uG Release(Hours) ug Release Released per Hour 0 0 0 0 0.5 2.14 2.14 4.28 3 1.73.84 0.68 4 0.28 4.12 0.28 6 0.26 4.38 0.13 24 2.05 6.43 0.11

Example 5

Multi-Link™ stents were cleaned by placement in an ultrasonic bath ofisopropyl alcohol solution for 10 minutes. The stents were dried andplasma cleaned in a plasma chamber. An EVOH solution was made with 1gram of EVOH and 7 grams of DMSO, making an EVOH:DMSO ratio of 1:7.Cephalotaxin was added to the 1:7 EVOH:DMSO solution. Cephalotaxinconstituted 5% by weight of the total weight of the solution. Thesolution was vortexed and placed in a tube. The cleaned Multi-Link™stents were attached to mandrel wires and dipped into the solution. Thecoated stents were passed over a hot plate, for about 3-5 seconds, witha temperature setting of about 60° C. The coated stents were cured for 6hours in an air box then placed in a vacuum oven at 60° C. for 24 hours.The above process was repeated twice, having a total of three layers.The average weight of the coating was 0.00013 gram, with an estimatedcephalotaxin concentration of 33 ug. The stents were sterilized byelectron beam radiation. Cephalotaxin/EVOH coated stents and EVOH-coatedcontrol stents were implanted in the coronary arteries of 4 pigs,generally in accordance to the procedure set forth in “Restenosis AfterBalloon Angioplasty-A Practical Proliferative Model in Porcine CoronaryArteries” by Robert S. Schwartz, et al., Circulation 82(6):2190-2200,December 1990, and “Restenosis and the Proportional Neointimal Responseto Coronary Artery Injury: Results in a Porcine Model” by Robert S.Schwartz et al, J Am Coll Cardiol; 19:267-74 Feb. 1992. Results of theporcine artery study indicated that there was no significant differencebetween the uncoated, EVOH coated and cephalotaxin coated stents in theamount of neointimal proliferation resulting from arterial injury.

Example 6

Multi-Link Duet™ stents (available from Guidant Corporation) werecleaned by placement in an ultrasonic bath of isopropryl alcoholsolution for 20 minutes, then air dried. An EVOH stock solution was madewith 1 gram of EVOH and 7 grams of DMSO, making an EVOH:DMSO ratio of1:7. The mixture was placed in a warm water shaker bath at 60° C. for 12hours. The solution was mixed, then cooled to room temperature. Aco-solvent was added to the EVOH solution to promote wetting of thestruts of the Multi-Link Duet™ stents. One gram of tetrahydrofuran (THF)was mixed with 1.2 grams of the EVOH: DMSO solution. The cleanedMulti-Link Duet™ stents were attached to mandrel wires and dipped intothe solution. The coated stents were passed over a hot plate, for about3 to 5 seconds, with a temperature setting of about 60° C. The coatedstents were then heated in a laboratory oven at 90° C. for 4 hours. Thethin EVOH coating adhered to stainless steel without peeling orcracking. EVOH forms a superior primer base coat for other polymers thatdo not adhere well to stainless steel.

Example 7

Multi-Link Duet™ stents were cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH solution was made with 1gram of EVOH and 5 grams of DMSO, making an EVOH:DMSO ratio of 1:5. Themixture was placed in a warm water shaker bath at 60° C. for 12 hours.The solution was mixed, then cooled to room temperature. The dissolvedEVOH:DMSO solution was mixed with 24.6 grams of THF and 19.56 grams ofDMSO. The solution was mixed then placed in the reservoir of an airpressured atomizing sprayer. Multi-Link Duet™ stents were sprayed whilethe stents rotated between 30 to 120 rpm. The spray time was dependentupon the flow rate of the sprayer. A flow rate between 1 to 20 mg/secondrequired a stent to be sprayed between 1 to 30 seconds. The polymercoated Multi-Link Duet™ stents were heated in a forced air convectionoven for 12 hours. The coatings were transparent, giving the Multi-LinkDuet™ stents a glossy-like shine.

Example 8

Multi-Link Duet™ stents were cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution was madehaving an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm watershaker bath at 60° C. for 12 hours. The solution was mixed, then cooledto room temperature. Various co-solvents were examined to determinewhich co-solvent would promote a thicker coating. These co-solvents wereTHF, DMF, 1-butanol, and n-butyl acetate. The formulation for theco-solvents was as follows. Three grams of dissolved EVOH: DMSO solutionwas mixed with 0.9 gram of THF; three grams of dissolved EVOH: DMSOsolution was mixed with 0.39 gram of DMF; three grams of dissolved EVOH:DMSO solution was mixed with 0.5 gram of 1-butanol; and three grams ofdissolved EVOH: DMSO solution was mixed with 0.68 gram of n-butylacetate. The cleaned Multi-Link Duet™ stents, attached to mandrel wires,were dipped into the solutions. The coated stents were passed over a hotplate, for about 3 to 5 seconds, with a temperature setting of about 60°C. The coated stents were heated in a forced air convection oven for 24hours. A second layer of coating was applied to coated Multi-Link Duet™stents and the stents were heated in the same manner as above. Nodifference was seen between the stents coated with the variousco-solvents (e.g., greater weight of coating or physical appearance).All coated stents were transparent, giving the Multi-Link Duet™ stents aglossy-like shine. No webbing or bridging of the coating was seenbetween the struts of the coated Multi-Link Duet™ stents. The weight ofthe coatings was between 0.2 to 0.27 mg/stent.

Example 9

Multi-Link Duet™ stents are cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution is madehaving an EVOH:DMSO ratio of 1:4. The mixture is placed in a warm watershaker bath at 60° C. for 12 hours. The solution is mixed, then cooledto room temperature. A 9% by weight Dexamethasone solution is formulatedas follows: 2.96 grams of the EVOH: DMSO solution is mixed with 0.29gram of Dexamethasone, then 0.9 gram of THF is added. The cleanedMulti-Link Duet™ stents are attached to mandrel wires and dipped intothe solution. The coated stents are passed over a hot plate, for about 3to 5 seconds, with a temperature setting of about 60° C. The coatedstents are cured in a forced air convection oven for 2 hours. A secondlayer of coating is applied and cured in the above manner. It ispredicted that the coatings will be transparent, giving the Multi-LinkDuet™ stents a glossy-like shine.

Example 10

Multi-Link Duet™ stents are cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution is madehaving an EVOH:DMSO ratio of 1:4. The mixture is placed in a warm watershaker bath at 60° C. for 12 hours. The solution is mixed, then cooledto room temperature. A 9% by weight Dexamethasone solution is formulatedas follows: 2.96 grams of the EVOH: DMSO solution is mixed with 0.29gram of Dexamethasone, then 0.9 gram of THF is added. The cleanedMulti-Link Duet™ stents are attached to mandrel wires and dipped intothe solution. The coated stents are passed over a hot plate, for about 3to 5 seconds, with a temperature setting of about 60° C. The coatedstents are cured in a forced air convection oven for 2 hours. A secondlayer of coating is applied and cured in the above manner. It ispredicted that the coatings will be transparent, giving the Multi-LinkDuet™ stents a glossy-like shine.

Example 11

Multi-Link Duet™ stents were cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution was madehaving an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm watershaker bath at 60° C. for 12 hours. The solution was mixed, then cooledto room temperature. A 4.75% by weight actinomycin D solution wasformulated as follows: 600 milligrams of the EVOH: DMSO solution wasmixed with 40 milligrams of actinomycin D, then 200 milligrams of THFwas added. The cleaned Multi-Link Duet™ stents were attached to mandrelwires and dipped into the solution. The coated stents were passed over ahot plate, for about 3 to 5 seconds, with a temperature setting of about60° C. The coated stents were cured in a forced air convection oven for2 hours. A second layer of coating was applied and cured in the abovemanner.

Example 12

Multi-Link Duet™ stents were cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution was madehaving an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm watershaker bath at 60° C. for 12 hours. The solution was mixed, then cooledto room temperature. A 3.60% by weight actinomycin D solution wasformulated as follows: 600 milligrams of the EVOH: DMSO solution wasmixed with 40 milligrams of actinomycin D, then 480 milligrams of DMFwas added. The cleaned Multi-Link Duet™ stents were attached to mandrelwires and dipped into the solution. The coated stents were passed over ahot plate, for about 3 to 5 seconds, with a temperature setting of about60° C. The coated stents were cured in a forced air convection oven for2 hours. A second layer of coating was applied and cured in the abovemanner.

Example 13

Multi-Link Duet™ stents were cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution was madehaving an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm watershaker bath at 60° C. for 12 hours. The solution was mixed, then cooledto room temperature. A 6.45% by weight actinomycin D solution wasformulated as follows: 680 milligrams of the EVOH: DMSO solution wasmixed with 80 milligrams of actinomycin D, then 480 milligrams of DMFwas added. The cleaned Multi-Link Duet™ stents were attached to mandrelwires and dipped into the solution. The coated stents were passed over ahot plate, for about 3 to 5 seconds, with a temperature setting of about60° C. The coated stents were cured in a forced air convection oven for2 hours. A second layer of coating was applied and cured in the abovemanner.

Example 14

Multi-Link Duet™ stents are cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution is madehaving an EVOH:DMSO ratio of 1:40. The mixture is placed in a warm watershaker bath at 60° C. for 12 hours. The solution is mixed, then cooledto room temperature. A 0.60% by weight actinomycin D solution can beformulated as follows: 4920 milligrams of the EVOH: DMSO solution ismixed with 40 milligrams of Actinomycin D, then 2000 milligrams of THFis added. The cleaned Multi-Link Duet™ stents can be sprayed upon by theabove formulation. The coated stents are cured in a forced airconvection oven for 2 hours. A second layer of coating is applied andcured in the above manner.

Example 15 Inhibition of SMC proliferation with Actinomycin D

Medial smooth muscle cells (SMC) were isolated from rat aorta andcultured according to explant methods known to one of ordinary skill inthe art. Cells were harvested via trypsinization and subcultivated.Cells were identified as vascular SMC through their characteristichill-and-valley growth pattern as well as indirect immunofluorescencewith monoclonal anti SMC α-actin. Studies were performed with cells atpassage 3-4. SMC monlayers were established on 24 well culture dishes,scrape wounded and treated with actinomycin D, mytomycin and docetaxel.The cells were exposed to the drug solution of different concentrationsfor 2 hours and then washed with buffered saline solution. Theproliferation of the cells was quantified by standard technique ofthymidine incorporation. The results from the study are tabulated inFIG. 5.

The IC₅₀ (concentration at which 50% of the cells stop proliferating) ofactimomycin D was 10⁻9M as compared to 5×10⁻5M for mitomycin and 10⁻6Mfor docetaxel. Actinomycin D was the most potent agent to prevent SMCproliferation as compared to other pharmaceutical agents.

Example 16 Reduction in Restenosis in the Porcine Coronary Artery Model

Porcine coronary models were used to assess the degree of the inhibitionof neointimal formation in the coronary arteries of a porcine stentinjury model by Actinomycin D, delivered with a microporous ballooncatheter (1×10⁶ pores/mm² with sizes ranging from 0.2-0.8 micron).

The preclinical animal testing was performed in accordance with the NIHGuide for Care and Use of Laboratory Animals. Domestic swine wereutilized to evaluate effect of the drug on the inhibition of theneointimal formation. Each testing procedure, excluding the angiographicanalysis at the follow-up endpoints, was conducted using steriletechniques. During the study procedure, the activated clotting time(ACT) was monitored regularly to ensure appropriate anticoagulation.Base line blood samples were collected for each animal before initiationof the procedure. Quantitative coronary angiographic analysis (QCA) andintravascular ultrasound (IVUS) analysis was used for vessel sizeassessment.

The vessels at the sites of the delivery were denuded by inflation ofthe PTCA balloons to 1:1 balloon to artery ratio and moving the balloonsback and forth 5 times. The drug was delivered to the denuded sites at3.5 atm (3.61 Kg/sq cm) for 2 minutes using the microporous ballooncatheters before stent deployment. The average volume of delivery wasabout 3.3+/−1.2 ml. Following drug delivery, stents were deployed at thedelivery site such that final stent to artery ratio was 1.1:1.

QCA and IVUS analyses were used for stent deployment guidance.Pre-stenting IVUS measurements of the lumen size at the targeted vesselsites were performed for determination of the balloon (size) inflationpressure. Quantitative analysis of the stented coronary arteries tocompare pre-stenting, post-stenting, follow-up minimal luminaldiameters, stent recoil, and balloon/stent to artery ratio wereperformed. Following stent implantation and final angiogram, all deviceswere withdrawn and the wounds closed; the animals were allowed torecover from anesthesia as managed by the attending veterinarian oranimal care professionals at the research center.

Upon return to the research laboratory at the 28-day endpoint,angiographic assessments were performed. Coronary artery blood flow wasassessed and the stented vessels were evaluated to determine minimallumen diameter. The animals were euthanized following this procedure atthe endpoint. Following euthanasia, the hearts were pressure perfusionfixed with formalin and prepared for histological analysis, encompassinglight microscopy, and morphometry. Morphometric analysis of the stentedarteries included assessment of the position of the stent struts anddetermination of vessel/lumen areas, percent (%) stenosis, injuryscores, intimal and medial areas and intima/media ratios. Percentstenosis is quantitated by the following equation:

100(IEL area−lumen area)/IEL area

where IEL is the internal elastic lamia.

The control group of animals received delivery of water instead of thedrug. The test group of animals received actinomycin D in two differentconcentration of 10⁻5M and 10 ⁻4M. The results of the study aretabulated in Table 4. The percent stenosis in the treated groups(32.3+/−11.7) was significantly decreased as compared to the controlgroups (48.8+/−9.8). FIGS. 6A and 6B illustrate sample pictures of thehistology slides of the coronary vessels from the control and the Dose 1group, respectively.

TABLE 4 t test CONTROL DOSE 1 DOSE 2 (significant 0M 1E−05M 1E−04M if p< 0.05) (n = 9) (n = 10) (n = 7) p~ p* ANGIOGRAPHIC DATA (QCA) PercentDiameter 48.8 +/− 9.8  36.8 +/− 9.7  32.3 +/− 11.7 0.02 0.01 Stenosis ttest CONTROL DOSE 1 DOSE 2 (significant 0M 1E−05M 1E−04M if p < 0.05) (n= 27) (n = 30) (n = 21) p~ p* HISTOMORPHOMETRIC DATA Percent Stenosis63.4 +/− 12.7 51.8 +/− 13.8 54.1 +/− 11.7 0.002 0.01 (IEL area-lumenarea)/IEL area Residual Lumen 0.36 +/− 0.16 0.49 +/− 0.14 0.46 +/− 0.080.002 0.01 (Lumen area)/IEL area ~comparison between control and Dose 1*comparison between control and Dose 2

The results of the in vitro and in vivo standard test proceduresdemonstrate that actinomycin D is useful for the treatment ofhyper-proliferative vascular disease. Specifically, actinomycin D isuseful for the inhibition of smooth muscle cell hyperplasia, restenosisand vascular occlusion in a mammal, particularly occlusions following amechanically mediated vascular trauma or injury.

Example 17

Multi-Link Duet™ stents (13 mm in length) were cleaned in an ultrasonicbath of isopropyl alcohol for 20 minutes, then air dried. An EVOH stocksolution was made having an EVOH:DMSO ratio of 1:4. The mixture wasplaced in a warm water shaker bath at 60° C. for 12 hours. The solutionwas mixed, then cooled to room temperature. A 5.06% by weightactinomycin D solution was formulated as follows: 40 milligrams ofactinomycin D was dissolved in 150 milligrams of THF, then 600milligrams of the EVOH: DMSO was added. The cleaned Multi-Link Duet™stents were attached to mandrel wires and dipped into the solution. Thecoated stents were passed over a hot plate, for about 3 to 5 seconds,with a temperature setting of about 60° C. The coated stents were curedin a forced air convection oven at 60° C. for 1 hour. A second layer ofcoating was applied in the above manner and cured in a forced airconvection oven at 60° C. for 4 hours. An average coating weight ofabout 260 micrograms and an average actinomycin D loading of about 64micrograms was achieved.

Example 18

Multi-Link Duet™ stents (13 mm in length) were cleaned in an ultrasonicbath of isopropyl alcohol for 20 minutes, then air dried. An EVOH stocksolution was made having an EVOH:DMSO ratio of 1:4. The mixture wasplaced in a warm water shaker bath at 60° C. for 12 hours. The solutionwas mixed, then cooled to room temperature. A 3.75% by weightactinomycin D solution was formulated as follows: 60 milligrams ofactinomycin D was dissolved in 310 milligrams of DMF, then 1.22 grams ofEVOH: DMSO solution was added. The cleaned Multi-Link Duet™ stents wereattached to mandrel wires and dipped into the solution. The coatedstents were passed over a hot plate, for about 3 to 5 seconds, with atemperature setting of about 60° C. The coated stents were cured in aforced air convection oven at 60° C. for 1 hour. A second layer ofcoating was applied in the above manner and cured in a forced airconvection oven at 60° C. for 4 hours. An average coating weight ofabout 270 micrograms with an average actinomycin D content of about 51micrograms was achieved.

Example 19

Multi-Link Duet™ stents were cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution was madehaving an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm watershaker bath at 60° C. for 12 hours. The solution was mixed, then cooledto room temperature. A 6.1% by weight actinomycin D solution wasformulated as follows: 100 milligrams of actinomycin D was dissolved in310 milligrams of DMF, then 1.22 grams of EVOH: DMSO was added. Thecleaned Multi-Link Duet™ stents were attached to mandrel wires anddipped into the solution. The coated stents were passed over a hotplate, for about 3 to 5 seconds, with a temperature setting of about 60°C. The coated stents were cured in a forced air convection oven at 60°C. for 1 hour. A second layer of coating was applied in the above mannerand cured in a forced air convection oven at 60° C. for 4 hours. Anaverage coating weight of about 250 micrograms and an averageactinomycin D loading of about 75 micrograms was achieved.

Example 20

Multi-Link Duet™ stents are cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution is madehaving an EVOH:DMSO ratio of 1:40. The mixture is placed in a warm watershaker bath at 60° C. for 12 hours. The solution is mixed, then cooledto room temperature. A 0.60% by weight actinomycin D solution can beformulated as follows: 4920 milligrams of the EVOH: DMSO solution ismixed with 40 milligrams of Actinomycin D, then 2000 milligrams of THFis added. The cleaned Multi-Link Duet™ stents can be sprayed upon by theabove formulation. The coated stents are cured in a forced airconvection oven 60° C. for 15 minutes. Additional layers of the coatingare applied and cured in the above manner. The final curing step for thecoated stents is conducted for about 4 hours.

Example 21

A stainless steel stent can be spray coated with a formulation of EVOHand a drug, as previously described in any of the above examples. Adiffusion barrier composition can be formulated with 2 grams of EVOHblended with 20 grams of dimethylsulfoxide. 2.2 grams of fumed silicacan be added and dispersed with a high shear process. With constantagitation, 50 grams of tetrahydrofuran and 30 grams of dimethylformamideare admixed with the blend. The stent, having the EVOH coating, can beimmersed in the diffusion barrier composition to form a layer.

Example 22

A stainless steel stent can be spray coated with a formulation of EVOHand a drug, as previously described in any of the above examples. Adiffusion barrier formulation can be made by dissolving 8 grams of EVOHinto 32 grams of dimethylsulfoxide. To this is added 14 grams of rutiletitanium dioxide and 7 grams more of dimethylsulfoxide. The particlescan be dispersed using a ball mill. The final solution is diluted with39 grams of tetrahydrofuran, added slowly with constant agitation. It ispredicted that the diffusion barrier will reduce the rate at which thedrug is released from the stent.

Example 23

A stainless steel stent can be coated with a formulation of EVOH and adrug, as previously described in any of the above examples. A diffusionbarrier formulation can be made by dissolving 8 grams of EVOH in 32grams of dimethylsulfoxide. 10.5 grams of solution precipitatedhydroxyapatite can be added to the blend. The particles can be dispersedusing a rotor stator mixer. With constant agitation, 30 grams oftetrahydrofuran can be added. The stent can be coated by immersionfollowed by centrifugation.

Examples 24

A stent can be coated with a formulation of EVOH and a drug, aspreviously described in any of the above examples. 8 grams of EVOH canbe added 50 grams of dimethylsulfoxide and the polymer can be dissolvedby agitation and heat. Four grams of lamp black can be added anddispersed in a ball mill. 60 grams of dimethyl sulfoxide and 110 gramsof tetrahydrofuran are slowly added while stirring. The stent can bespray coated.

Example 25

A stent can be coated with a formulation of EVOH and a drug, aspreviously described in any of the above examples. Colloidal gold can beprepared by reduction of tetrachloroauric acid with sodium citrate inaqueous solution. The solution can be exchanged by rinsing withtetrahydrofuran. Eight grams of EVOH can be dissolved in 32 grams ofdimethylsulfoxide. To this is added a solution of 77 grams of colloidalgold in 32 grams of tetrahydrofuran. The stent can be coated by a dipcoating process.

Example 26

In vivo data is provided illustrated positive remodeling caused by theapplication of actinomycin D. Stents coated with EVOH impregnated withactinomycin D and a control group of stents coated with EVOH free fromactinomycin D were implanted in porcine coronary arteries. The animalswere sacrificed at the end of 28 days. The EEL area of the actinomycinD-loaded vessels was statistically significantly greater than the EELarea of the control vessels. The index of remodeling was 1.076(8.54/7.94).

Condition Mean Area Std Dev IEL Drug coated(Act-D in EVOH) 7.47 0.89Control (EVOH) 6.6 0.61 p value 0.0002 Statistical significantdifference EEL (external elastic lamia) Drug coated(Act-D in EVOH) 8.540.87 Control (EVOH) 7.94 0.73 p value 0.014 Statistical significantdifference

EEL Area (mm²) ID # Control ID # Actinomycin D ID # EVOH 48 LCX d 6.396663 LCX d 7.4498 63 LAD d 8.3037 48 LCX m 7.4601 63 LCX m 8.2509 63 LAD m8.8545 48 LCX p 7.3063 63 LCX p 7.7342 63 LAD p 9.4698 49 LAD d 8.557363 RCA d 7.9207 64 LCX d 7.8063 49 LAD m 8.5187 63 RCA m 6.9926 64 LCX m7.1117 49 LAD p 6.6346 63 RCA p 8.3883 64 LCX p 7.2411 58 LAD d 8.607865 LAD d 7.8546 64 RCA d 8.3383 58 LAD m 8.1674 65 LAD m 9.2545 64 RCA m8.0793 58 LAD p 8.3775 65 LAD p 9.2515 64 RCA p 8.3652 59 LCA d 8.305468 LAD d 8.7854 65 LCX d 6.4638 59 LCX m 7.3713 68 LAD m 9.5164 65 LCX m7.1493 59 LCX p 7.8662 68 LAD p 9.1504 65 RCA d 8.5955 59 RCA d 7.371469 LCX d 9.6679 65 RCA m 8.0855 59 RCA m 6.6783 69 LCX m 9.1237 65 RCA p8.4785 59 RCA p 7.4707 69 LCX p 9.9849 68 LCX d 8.4723 62 LCX d 7.878469 RCA d 9.4765 68 LCX m 7.8382 62 LCX m 7.5318 69 RCA m 7.4424 68 LCX p8.0570 62 LCX p 6.2647 69 RCA p 9.1462 68 RCA d 8.4840 62 RCA d 8.324070 LCX d 8.9504 68 RCA p 8.8767 62 RCA m 7.9535 70 LCX m 8.9117 69 LAD d6.6648 62 RCA p 8.5454 70 LCX p 8.7533 69 LAD m 6.8614 67 LAD d 8.953270 RCA d 7.3249 69 LAD p 7.7632 67 LAD m 9.2410 70 RCA m 7.1061 70 LAD d7.5175 67 LAD p 8.3841 70 RCA p 8.5830 70 LAD m 7.8630 70 LAD p 8.2222AVG 7.8402 8.5425 7.9475 SD 0.8046 0.8755 0.7349

ActD vs EVOH p = 0.014709 AVG % EEL growth 7.486304

IEL Area (mm2) ID # Control ID # Actinomycin D ID # EVOH 48 LCX d 5.217863 LCX d 6.3785 63 LAD d 6.9687 48 LCX m 6.2108 63 LCX m 7.5206 63 LAD m7.3908 48 LCX p 6.1125 63 LCX p 6.9992 63 LAD p 7.3563 49 LAD d 7.284863 RCA d 6.9632 64 LCX d 6.4420 49 LAD m 7.4117 63 RCA m 6.0418 64 LCX m6.0064 49 LAD p 5.9918 63 RCA p 7.4794 64 LCX p 5.9970 58 LAD d 7.204965 LAD d 6.2324 64 RCA d 6.8001 58 LAD m 6.9334 65 LAD m 8.3785 64 RCA m6.8561 58 LAD p 6.9454 65 LAD p 8.5819 64 RCA p 7.0172 59 LCA d 7.264068 LAD d 8.0964 65 LCX d 5.2485 59 LCX m 6.2014 68 LAD m 8.6879 65 LCX m6.1135 59 LCX p 6.7283 68 LAD p 8.0914 65 RCA d 7.1525 59 RCA d 6.051969 LCX d 8.7181 65 RCA m 6.4815 59 RCA m 5.9992 69 LCX m 8.0273 65 RCA p7.1775 59 RCA p 5.9032 69 LCX p 8.5222 68 LCX d 6.9571 62 LCX d 6.532969 RCA d 8.3796 68 LCX m 6.5724 62 LCX m 6.2804 69 RCA m 6.4219 68 LCX p6.7740 62 LCX p 4.9303 69 RCA p 7.7757 68 RCA d 7.2425 62 RCA d 7.097770 LCX d 7.5392 68 RCA p 7.5554 62 RCA m 6.7466 70 LCX m 7.6573 69 LAD d5.5505 62 RCA p 7.1747 70 LCX p 6.9749 69 LAD m 5.5571 67 LAD d 8.026470 RCA d 6.2815 69 LAD p 6.2697 67 LAD m 8.1144 70 RCA m 5.9760 70 LAD d6.3212 67 LAD p 7.2091 70 RCA p 7.6195 70 LAD m 6.6518 70 LAD p 6.9032AVG 6.6489 7.4727 6.6025 SD 0.7883 0.8972 0.6130

ActD vs EVOH p = 0.000283 AVG % IEL growth 13.17981

FIGS. 7A and 7B illustrate sample pictures of the histology slides ofthe coronary vessels from the control group 64 RCA (Right CoronaryGroup) and the actinomycin D loaded stent group 68 LAD (Left AnteriorDescending), respectively. The stent used was an Advanced CardiovascularSystems Multi-Link Duet™ (stainless steel). As is illustrated by FIG.7B, the positive remodeling of EEL 50, caused by the application ofactinomycin D, creates a gap between stent struts 52 and EEL 50.Thrombus deposites, illustrated by reference number 54, are formed inthe gap over time. The use of a self-expandable stent eliminates theformation of the gap as the stent self-expands in response to thepositive remodeling of IEL. Thrombus deposits can be, accordingly,eliminated.

Actinomycin D induces the positive remodeling of the vessel walls, moreparticularly positive remodeling of the external elastic lamina (EEL) ofa blood vessel wall. Positive remodeling is generally defined as theability of the vessel walls to structurally adapt, by increasing inlumen size, to chronic stimuli. A positively remodeled lumen wall has agreater diameter or size as compared to a lumen wall which has not beensubjected to the remodeling effect. Accordingly, the flow of bloodthrough the remodeled site is increased—flow which would have otherwisebeen reduced because of, for example, the presence of plaque build-up ormigration and proliferation of cells. The index of remodeling is definedby the ratio of the area circumscribed by the EEL of the lesion site tothe area circumscribed by the EEL of a reference site. As a result ofthe positive remodeling of the EEL, the internal elastic lamina (IEL),in response, can also increases in area or diameter. Actinomycin D, oranalogs or derivative thereof, not only can inhibit abnormal orinappropriate migration and/or proliferation of smooth muscle cells,which can lead to restenosis, but can also induce positive remodeling ofthe blood vessel walls. Thus the widening of the diseased region becomesmore pronounced.

Example 27

2 grams of an acrylate terminated urethane (Henkel 12892) can be addedto 18 grams of ethyl acetate with 0.08 grams of benzophenone and 0.08grams of 1-hydroxycyclohexyl phenyl ketone. After application, the stentcan be cured for 5 minutes under medium pressure mercury lamp.

Example 28

For a thermoset system, 1.67 grams of Epon 828 (Shell) resin can beadded to 98 grams of propylene glycol monomethyl ether and 0.33 grams ofJeffamine T-430 (Huntsman). After application, the stent can be bakedfor 2 hours at 80° C. and 2 hours at 160° C.

Example 29

A 0.25% (w/w) solution of tetra-n-butyl titanate can be made inanhydrous ethyl acetate. The solution can be applied by spraying to asurface of a stainless steel stent. The stent can be heated at 100° C.for two hours.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects and, therefore, the appended claims areto encompass within their scope all such changes and modifications asfall within the true spirit and scope of this invention.

Example 30 Objective

Coated stents tested through simulated delivery to a target lesion fortesting the mechanical integrity of the coating.

Group Quantity Coating A 2 Control: 2% EVAL in 1:1 THF:DMSO, 3:1EVAL:Act-d; no primer B 2 2% EVAL in 5:3:2 THF:DMF:DMSO, 3:1 EVAL:Act-d;no primer C 2 EVAL primer layer baked at 120 C/60 C for 2/10 hrs + 2%EVAL in 1:1 THF:DMSO, 3:1 EVAL:Act-d; primer D 2 EVAL primer layer bakedat 140 C/60 C for 2/2 hrs + 2% EVAL in 1:1 THF:DMSO, 3:1 EVAL:Act-d;primer

Background

In this experiment four different treatment groups were tested through asimulated delivery and use. Number of peel defects at rings 3, 5, and 7,with a peel defect defined as a location on the stent where coating hasbeen removed to expose bare stent or an underlying layer of coating,were observed.

Materials and Equipment

1. 8, 13 mm Solo stents (Available from Guidant Corporation);

2. 8, 3.0×30 mm Duet catheters;

3. 100% IPA;

4. Tominator Stent Crimper S/N 400;

5. 7F JL4 guiding catheter;

6. 0.014″ Balance Middle Weight guide wire;

7. Rotating Hemostatic Valve;

8. SVS tortuosity tree (2.5 mm lumen tapering to 1.5 mm lumen);

Preparation

Crimped the stents onto the catheters using the Tominator crimper andthe following conditions: 3 crimps, 65 psi, rotation between crimps.

Test Procedure

-   1. Performed simulation using heart model having a tortuosity and    contained in a tub filled with water:    -   a. Inserted the stents through the following set-up: RHF, 7F JL4        guiding catheter, SVS tortuosity tree (2.5 mm lumen at entrance,        1.5 mm lumen at exit).    -   b. Once the stent passed through the distal opening of        tortuosity, the balloon was cut from the catheter just distal to        proximal marker.-   2. Examined the stents under 100× magnification using Leica MZFLIII    microscope in the clean environment room (CER).-   3. Recorded number of peel defects at stent rings 3, 5, and 7. Only    the outer diameter (“OD”) was examined for peel defects.-   4. All test samples were handled with personal protective equipment    (PPE) appropriate for drug containing stents.

Data Summary and Results

Group # Peel Defects/Ring Comments A (THF) 2.0 — B (DMF) 5.3 Began withpoor coating finish. C (140° C.) 0.7 — D (120° C.) 0 —

Discussion

The test was performed to observe the coating integrity after asimulated delivery to a tortuosity without a lesion. The primer layerimproved coating adhesion to the stents that resulted in fewer defectsafter a simulated use. Group B had a number defects. Although thecoating surface for Group B was poor to begin with, and the defects werenot too severe.

Example 31 Objective

The adhesion of 0.67% Actinomycin-D (in 5% EVAL 1:1 THF:DMSO solution)coating on stents with two different surface treatments was compared tocontrol samples. The specific surface treatments consisted of: (1) Argonplasma treatment; and (2) Argon plasma treatment with a primer layer of5% EVAL in 1:1 DMSO:DMF solution applied with the dip-spin process,i.e., centrifugation process, and followed by heat treatments at 120° C.for two hours and 60° C. for 10 hours. The test method used to testadhesion of coatings on stents was a wet flow test, expanding the stentsin a Tecoflex tubing at 37° C. of water or saline. Water or saline isthen flushed through the stents for 18 hours to simulate blood flowthrough the stents. The stents were then removed from the Tecoflex witha “stent catcher” and observed under optical microscope for defects.

Group Treatment Flow Rate A None  50 mL/min B Argon plasma  50 mL/min CArgon plasma + 5% EVAL in 1:1 DMSO:DMF  50 mL/min heated at 120° C. fortwo hours and 60° C. for 10 hours D None 100 mL/min E Argon plasma 100mL/min F Argon plasma + 5% EVAL in 1:1 DMSO:DMF 100 mL/min heated at120° C. for two hours and 60° C. for 10 hours

Materials and Equipment

-   -   1. 30, 13 mm coated Solo stents, cleaned ultrasonically in IPA        for 15 minutes;    -   2. 30, balloon catheters or subassemblies to expand the stents        (3.0×20 mm RX Rocket);    -   3. 0.67% Actinomycin-D in 5% EVAL with 1:1 THF:DMSO solution;    -   4.5% EVAL in 1:1 DMF:DMSO;    -   5. 3.0 mm, thin walled Tecoflex tubing;    -   6. Saline;    -   7. Lint Free Wipes SU 00126 or equivalent;    -   8. 100% IPA;    -   9. Oven;    -   10. Timer;    -   11. Centrifuge;    -   12. Plasma Machine (available from Advanced Plasma System);    -   13. Ultrasonic cleaner;    -   14. Mettler balance with 0.1 micrograms resolution; and    -   15. Spray Coater with Fan Air Cap and EFD dispenser (EFD Inc.        East Providence R.I.).

Preparation

1. Sonicated the stents in IPA for 15 minutes;2. Weighed each stent to the nearest microgram;3. Prepared 5 stent samples:

A. Groups A and D:

-   -   i. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blowing.    -   ii. Weighed each sample at the end of the last pass to the        nearest microgram.    -   iii. Baked the samples for 4 hrs at 60° C.    -   iv. Placed the stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. saline.

B. Groups B and E:

-   -   i. Placed the samples on a sample holder. Performed argon plasma        treatment using plasma machine.    -   ii. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   iii. Weighed each sample at the end of the last pass to the        nearest microgram.    -   iv. Baked the samples for 4 hrs at 60° C.    -   v. Placed the stents into the Tecoflex tubing with the balloon        catheter-1-submerged in 37° C. saline.

C. Groups C and F:

-   -   i. Placed samples flat on a sample holder. Performed argon        plasma treatment.    -   ii. Used dip-spin process to apply 2% EVAL primer layer, 1:1        DMSO:DMF.    -   iii. Baked the stents at 120° C. for two hours.    -   iv. Baked the stents at 60° C. for ten hours.    -   v. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 4 hrs at 60° C.    -   viii. Placed the stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

Test Procedure

Tested three samples from each group. Wet Flow Testing:

-   1. Expanded the stents into the 3.0 mm Tecoflex tubing in 37° C.    saline.-   2. Performed wet flow testing for 18 hrs.-   3. Removed the stents from the Tecoflex tubing with a stent catcher.-   4. Count defects, based on the following categories: Defect type;    defect size; defect location; and peel defects on rings 3, 5, and 7.-   5. Stent weight could not be a measurable because of the loss of the    drug and uptake of water.-   6. All test samples were handled with PPE appropriate for drug    containing stents.

Data Summary

Average # of Peel Average # Peel Defects/Stent (3 Defects/Ring AfterFlow Group rings) After Flow Test Test A 18.0 6.0 B 15.3 5.1 C 2.7 0.9 D14.3 4.8 E 14.0 4.7 F 0.7 0.2

Discussion

Peel defects are defined as areas where the coating separated from thestent. The number of peel defects were counted on the stents'OD/sidewall on rings 3, 5, and 7. The flow field was on the innerdiameter (“ID”) of the stents' surface. Some of the damage to the ODsurface could have been aggravated by the Tecoflex tubing. The number ofpeel defects observed on groups C and F (EVAL primer) was clearly lowerthan the other two test groups, regardless of flow rate. The increasedflow rate did not induce more peel defects.

Example 32 Objective

The objective of this experiment was to test the adhesive properties ofan Actinomycin-D containing coating on stainless steel stents having anEVAL primer layer. The coated stents were tested in a wet flow testcondition of saline heated to 37° C. The number of “peel defects” on aselect number of stent rings was observed. A “peel defect” is defined asa location on the stent surface devoid of coating, i.e., bare metal orunderlying coating layer that is visible under optical magnification ofless than 100×.

Group Treatment Flow Rate A Argon plasma treatment + EVAL primer layer50 mL/min (15% EVAL, 1:1 DMF:DMSO) baked at 140° C. for 2 hours anddried at 60° C. for 2 hours B Argon plasma treatment + EVAL primer layer50 mL/min Control (15% EVAL, 1:1 DMF:DMSO) baked at 120° C. for 2 hoursand dried at 60° C. for 10 hours

Materials and Equipment

1. 10, 13 mm Solo stents, cleaned ultrasonically in IPA for 15 minutes;

2. 10, balloon catheters or subassemblies to expand the stents;

3. 15% EVAL in 1:1 DMF:DMSO solution;

4. Actinomycin-D solution, 1:1 THF:DMSO with 3:1 EVAL:Act-D;

5. Tecoflex tubing

6. Saline

7. Lint Free Wipes SU 00126 or equivalent

8. 100% IPA

9. Oven

10. Timer

11. Plasma Machine (Advanced Plasma System);

12. Ultrasonic cleaner; and

13. Mettler balance with 0.1 micrograms resolution.

Preparation

1. Sonicated the stents in IPA for 15 minutes.2. Weighed each stent to the nearest microgram.3. Prepared 5 stent samples for each group:

A. Group A (Control):

-   -   i. Placed the samples flat on a sample holder. Performed argon        plasma treatment.    -   ii. Used dip-spin process, i.e., centrifugation at 6000 rpm for        one minute, to apply the EVAL primer layer, 1:1 DMSO:DMF.    -   iii. Baked the stents at 140° C. for two hours in the convection        oven.    -   iv. Took weight measurements of each stent to the nearest        microgram.    -   v. Baked the stents at 60° C. for two hours in vacuum oven.    -   vi. Took weight measurements of each stent to the nearest        microgram.    -   vii. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   viii. Weighed each sample at the end of the last pass to the        nearest microgram.    -   ix. Baked samples for 4 hrs at 60° C.    -   x. Took weight measurements of each stent to the nearest        microgram.    -   xi. Placed the stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

B. Groups B:

-   -   i. Placed samples flat on sample holder. Performed argon plasma        treatment.    -   ii. Used dip-spin process at 6000 rpm for one minute to apply        EVAL primer layer, 1:1 DMSO:DMF.    -   iii. Baked the stents at 120° C. for two hours in the convection        oven.    -   iv. Took weight measurements on each stent to the nearest        microgram.    -   v. Baked the stents at 60° C. for ten hours in vacuum oven.    -   vi. Took weight measurements for each stent to the nearest        microgram.    -   vii. Performed spray-coating process in CER at the following        conditions: 3 passes, 3-second spray, no blow.    -   viii. Weighed each sample at the end of the last pass to the        nearest microgram.    -   ix. Baked the samples for 4 hrs at 60° C.    -   x. Took weight measurements of each stent to the nearest        microgram.    -   xi. Placed the stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

Test Procedure

-   -   1. Performed wet flow testing overnight for about 18 hrs.    -   2. Removed the stents from the Tecoflex tubing with a stent        catcher.    -   3. Counted the defects based on the number of peel defects at        rings 3, 5, and 7 on the stents' OD. Count the defects on the ID        of the same rings.    -   4. The weight could not be measured because of the loss of the        drug and uptake of water.    -   5. All test samples were handled with PPE appropriate for drug        containing stents.

Data Summary and Results

# Peel Average # of Peel # Peel Average # of Defects Defects/Ring (OD,Defects Peel Defects/Ring Group (OD) rings 3, 5, 7) (ID) (ID, rings 3,5, 7) A 0 0 1 0.3 0 0 1 0.3 0 0  1* 0.3 B 0 0 0 0 0 0 0 0 0 0 0 0*Defect occurred at a location of a defect in the stent surface.

Example 33 Objective

The objective of this study was to test the adhesive properties of anActinomycin-D containing coating on stainless steel stents having anEVAL primer layer. The coated stents were tested under wet flowconditions of saline heated to 37° C. The number of “peel defects” on aselect number of stent rings was observed. A “peel defect” is defined asa location on the stent surface devoid of coating, i.e., bare metal oran underlying coating layer that is visible under optical magnificationof no more than 100×.

Group Treatment Flow Rate A None 50 mL/min Control B Argon plasmatreatment + EVAL primer layer by 50 mL/min dip-spin (2% EVAL, 1:1DMF:DMSO) baked at 140° C. for 4 hours C EVAL primer layer by dip-spin(2% EVAL, 1:1 50 mL/min DMF:DMSO) baked at 140° C. for 4 hours D Argonplasma treatment + EVAL primer layer 50 mL/min by spray (2% EVAL, 1:1DMF:DMSO) baked at 140° C. for 4 hours E EVAL primer layer by spray (2%EVAL, 1:1 50 mL/min DMF:DMSO) baked at 140° C. for 4 hours

Materials and Equipment

1. 25, 13 mm Solo stents, cleaned ultrasonically in IPA for 15 minutes;

2. 25, balloon catheters or subassemblies to expand the stents;

3. 2% EVAL in 1:1 DMF:DMSO solution;

4. Actinomycin-D solution, 1:1 THF:DMSO with 3:1 EVAL:Act-D;

5. 3.0 mm Tecoflex tubing;

6. Saline;

7. Lint Free Wipes SU 00126 or equivalent;

8. 100% IPA;

9. Convection Oven

10. Timer;

11. Plasma Machine;

12. Ultrasonic cleaner; and

13. Mettler balance with 0.1 micrograms resolution.

Preparation

1. Sonicated the stents in IPA for 15 minutes.2. Weighed each stent to the nearest microgram.3. Prepared 5 stent samples for each group.

A. Group A (Control):

-   -   i. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   ii. Weighed each sample at the end of the last pass to the        nearest microgram.    -   iii. Baked the samples for 4 hrs at 60° C.    -   iv. Took the weight measurements of each stent to the nearest        microgram.    -   v. Placed the stents into the Tecoflex tubing with the balloon        catheter—submerged in 37° C. water.

B. Group B:

-   -   i. Placed samples flat on sample holder. Perform argon plasma        treatment.    -   ii. Used dip-spin process to apply EVAL primer layer, 1:1        DMSO:DMF (6000 rpm for one minute).    -   iii. Baked the stents at 140° C. for 4 hours in convection oven.    -   iv. Took weight measurements on each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER at the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 4 hrs at 60° C.    -   viii. Took the weight measurements of each stent to the nearest        microgram.    -   ix. Placed the stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

C. Group C:

-   -   i. Used dip-spin process to apply EVAL primer layer, 1:1        DMSO:DMF (6000 rpm for one minute).    -   ii. Baked the stents at 140° C. for four hours in convection        oven.    -   iii. Took weight measurements on each stent to the nearest        microgram.    -   iv. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   v. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vi. Baked the samples for 4 hrs at 60° C.    -   vii. Took weight measurements of each stent to the nearest        microgram.    -   viii. Placed stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

D. Group D:

-   -   i. Placed the samples flat on a sample holder. Perform argon        plasma treatment.    -   ii. Spray coated primer layer (2% EVAL, 1:1 DMF:DMSO) onto the        stents. Used 1.5 sec. spray time, 1-2 passes to achieve 10-40        micrograms of coating.    -   iii. Baked the stents at 140° C. for 4 hours in the convection        oven.    -   iv. Took weight measurements on each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER at the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked samples for 4 hrs at 60° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

E. Group E:

-   -   i. Spray coated primer layer (2% EVAL, 1:1 DMF:DMSO) onto the        stents. Used 1.5 sec. spray time, 1-2 passes to achieve 10-40        micrograms of coating.    -   ii. Baked the stents at 140° C. for four hours in convection        oven.    -   iii. Took weight measurements on each stent to the nearest        microgram.    -   iv. Performed spray-coating process in CER at the following        conditions: 3 passes, 3-second spray, no blow.    -   v. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vi. Baked the samples for 4 hrs at 60° C.    -   vii. Took weight measurements of each stent to the nearest        microgram.    -   viii. Placed the stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

Test Procedure

-   -   1. Performed wet flow testing overnight for about 18 hrs.    -   2. Removed stents from the Tecoflex tubing with a stent catcher.    -   3. Counted the defects based on the number of peel defects at        rings 1, 3, 5, and 7 on the stents' OD. Count the defects on the        ID of the same rings.    -   4. Stent weight could not be a measurable because of the loss of        the drug and uptake of water.    -   5. All test samples were handled with PPE appropriate for drug        containing stents.

Data Summary and Results

Group Defects/Ring (OD) Defects/Ring (ID) Control 2.67 3.00 Dip/Plasma0.67 0.47 Dip/No Plasma 0.87 0.80 Spray/Plasma 0.47 0.80 Spray/No Plasma0.67 0.73

Discussion

Peel Defects of Primer Coated Stents vs. Untreated Controls

An improved adhesion, based on the number of peel defects, of the drugcontaining coating to the Tri-Star stent when an EVAL primer layer wasapplied is illustrated. All four treatment groups displayedsignificantly fewer peel defects per stent than the untreated controlstents. Use of a spray-coated, 2% EVAL solution in 1:1 DMF:DMSO as aprimer significantly improved adhesion of Actinomycin-D containingcoating to the Tri-Star stents vs. the controls. The spray-coated primerproduced slightly higher peel defect counts compared to the dip-spindeposited primer.

Example 34 Objective

The objective of this experiment was to test the adhesive properties ofan Actinomycin-D containing coating to stainless steel stents having anEVAL primer layer. More specifically, this experiment attempted toillustrate the effect of different bake times on the final result. Thecoated stents were tested under wet flow conditions of saline heated to37° C. The number of “peel defects” on a select number of stent ringswas observed.

Group Treatment Flow Rate A none 50 mL/min Control B Argon plasmatreatment + EVAL primer layer by 50 mL/min spray (2% EVAL, 1:1 DMF:DMSO)baked at 140° C. for 15 minutes C Argon plasma treatment + EVAL primerlayer by 50 mL/min spray (2% EVAL, 1:1 DMF:DMSO) baked at 140° C. for 30minutes D Argon plasma treatment + EVAL primer layer by 50 mL/min spray(2% EVAL, 1:1 DMF:DMSO) baked at 140° C. for 60 minutes E Argon plasmatreatment + EVAL primer layer by 50 mL/min spray (2% EVAL, 1:1 DMF:DMSO)baked at 140° C. for 120 minutes

Materials and Equipment

1. 25, 13 mm Solo stents, cleaned ultrasonically in IPA for 15 minutes;

2. 25, balloon catheters or subassemblies to expand the stents;

3.2% EVAL in 1:1 DMF:DMSO solution;

4. Actinomycin-D solution, 1:1 THF:DMSO with 3:1 EVAL:Act-D;

5. 3.0 mm Tecoflex tubing;

6. Saline;

7. Lint Free Wipes SU 00126 or equivalent;

8. 100% IPA;

9. Convection Oven;

10. Timer;

11. Plasma Machine;

12. Ultrasonic cleaner; and

13. Mettler balance with 0.1 micrograms resolution.

Preparation

1. Sonicated stents in IPA for 15 minutes.2. Weighed each stent to the nearest microgram.3. Prepared 5 stent samples for each group.

A. Group A (Control):

-   -   i. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   ii. Weighed each sample at the end of the last pass to the        nearest microgram.    -   iii. Baked the samples for 240 minutes at 50° C.    -   iv. Took weight measurements of each stent to the nearest        microgram.    -   v. Placed the stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

B. Group B:

-   -   i. Placed samples flat on sample holder. Perform argon plasma        treatment.    -   ii. Spray coated primer layer (2% EVAL, 1:1 DMF:DMSO) onto        stents. Used 1.5 sec. spray time, 1-2 passes to achieve 10-40        micrograms of coating.    -   iii. Baked the stents at 140° C. for 15 minutes in the        convection oven.    -   iv. Took weight measurements on each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

C. Group C:

-   -   i. Placed the samples flat on sample holder. Perform argon        plasma treatment.    -   ii. Spray coated primer layer (2% EVAL, 1:1 DMF:DMSO) onto        stents. Used 1.5 sec. spray time, 1-2 passes to achieve 10-40        micrograms of coating.    -   iii. Baked the stents at 140° C. for 30 minutes in the        convection oven.    -   iv. Took weight measurements on each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

D. Group D:

-   -   i. Placed samples flat on sample holder. Perform argon plasma        treatment.    -   ii. Spray coated primer layer (2% EVAL, 1:1 DMF:DMSO) onto        stents. Used 1.5 sec. spray time, 1-2 passes to achieve 10-40        micrograms of coating.    -   iii. Baked the stents at 140° C. for 60 minutes in the        convection oven.    -   iv. Took weight measurements on each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

E. Group E:

-   -   i. Placed samples flat on sample holder. Perform argon plasma        treatment.    -   ii. Spray coated primer layer (2% EVAL, 1:1 DMF:DMSO) onto        stents. Used 1.5 sec. spray time, 1-2 passes to achieve 10-40        micrograms of coating.    -   iii. Baked the stents at 140° C. for 120 minutes in the        convection oven.    -   iv. Took weight measurements on each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER at the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed stent into the Tecoflex tube with balloon        catheter—submerged in 37° C. water.

Test Procedure

-   -   1. Performed wet flow testing overnight for about 18 hrs.    -   2. Removed the stents from the Tecoflex tubing with a stent        catcher.    -   3. Counted the defects based on the number of peel defects at        rings 3, 5, and 7 on the stents' OD. Count the defects on the ID        of the same rings.    -   4. Stent weight could not be a measurable because of the loss of        the drug and uptake of water.    -   5. All test samples were handled with PPE appropriate for drug        containing stents.

Data Summary and Results

Group Total Defects per Stent Control 3.33  15 min bake 1.00  30 minbake 3.00  60 min bake 1.67 120 min bake 1.33

Discussion

The control group with no primer layer had significantly more peeldefects as compared to the treatment groups with a primer layer. Thegroups with shorter baking times (15 and 30 minutes) had higher defectcounts than the groups with longer baking times.

Example 35 Objective

The objective of this experiment was to test the adhesive properties ofan Actinomycin-D containing coating on stainless steel stents having anEVAL primer layer. More specifically, different solvent systems (e.g.,THF and DMF) were evaluated. The coated stents were tested under wetflow conditions of saline heated to 37° C. The number of “peel defects”on a select number of stent rings was observed.

Group Treatment Flow Rate A none 50 mL/min Control B Argon plasmatreatment + EVAL primer layer 50 mL/min by spray (2% EVAL, 1:1 DMF:DMSO)baked at 140° C. for 15 minutes C Argon plasma treatment + EVAL primerlayer 50 mL/min by spray (2% EVAL, 1:1 DMF:DMSO) baked at 140° C. for 60minutes D Argon plasma treatment + EVAL primer layer 50 mL/min by spray(2% EVAL, 1:1 DMF:DMSO) baked at 140° C. for 240 minutes E Argon plasmatreatment + EVAL primer layer 50 mL/min by spray (2% EVAL, 1:1 THF:DMSO)baked at 140° C. for 60 minutes

Materials and Equipment

1. 25, 13 mm Solo stents, cleaned ultrasonically in IPA for 15 minutes;

2. 25, balloon catheters or subassemblies to expand the stents;

3. 2% EVAL in 1:1 DMF:DMSO solution;

4. 2% EVAL in 1:1 THF:DMSO solution;

5. Actinomycin-D solution, 1:1 THF: DMSO with 3:1 EVAL:Act-D, 2% EVAL;

6. 3.0 mm Tecoflex tubing;

7. Saline;

8. Lint Free Wipes SU 00126 or equivalent;

9. 100% IPA;

10. Convection Oven;

11. Timer;

12. Plasma Machine;

13. Ultrasonic cleaner; and

14. Mettler balance with 0.1 micrograms resolution.

Preparation

1. Sonicated stents in IPA for 15 minutes.2. Weighed each stent to the nearest microgram.3. Prepared 5 stent samples for each group.

A. Group A (Control):

-   -   i. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   ii. Weighed each sample at the end of the last pass to the        nearest microgram.    -   iii. Baked samples for 240 minutes at 50° C.    -   iv. Took weight measurements of each stent to the nearest        microgram.    -   v. Placed the stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

B. Group B:

-   -   i. Placed samples flat on a sample holder. Performed argon        plasma treatment.    -   ii. Spray coated the primer layer (2% EVAL, 1:1 DMF:DMSO) onto        the stents. Used 1.5 sec. spray time, 1-2 passes to achieve        10-40 micrograms of coating.    -   iii. Baked the stents at 140° C. for 15 minutes in the        convection oven.    -   iv. Took weight measurements of each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed the stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

C. Group C:

-   -   i. Placed samples flat on a sample holder. Performed argon        plasma treatment.    -   ii. Spray coated the primer layer (2% EVAL, 1:1 DMF:DMSO) onto        the stents. Used 1.5 sec. spray time, 1-2 passes to achieve        10-40 micrograms of coating.    -   iii. Baked the stents at 140° C. for 60 minutes in the        convection oven.    -   iv. Took weight measurements of each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed the stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

D. Group D:

-   -   i. Placed samples on flat on a sample holder. Performed argon        plasma treatment.    -   ii. Spray coated the primer layer (2% EVAL, 1:1 DMF:DMSO) onto        the stents. Used 1.5 sec. spray time, 1-2 passes to achieve        10-40 micrograms of coating.    -   iii. Baked the stents at 140° C. for 240 minutes in the        convection oven.    -   iv. Took weight measurements of each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER at the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed the stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

E. Group E:

-   -   i. Placed samples flat on a sample holder. Perform argon plasma        treatment.    -   ii. Spray coated the primer layer (2% EVAL, 1:1 THF: DMSO) onto        the stents. Used 1.5 sec. spray time, 1-2 passes to achieve        10-40 micrograms of coating.    -   iii. Baked the stents at 140° C. for 60 minutes in the        convection oven.    -   iv. Took weight measurements of each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER under the following        conditions: 3 passes, 3 second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed the stents into the Tecoflex tubing with a balloon        catheter—submerged in 37° C. water.

Test Procedure

-   -   1. Performed wet flow testing overnight for about 18 hrs.    -   2. Removed the stents from the Tecoflex tubing with a stent        catcher.    -   3. Counted the defects, based on the number of peel defects at        rings 3, 5, and 7 on the stents' OD. Counted defects on the ID        of the same rings.    -   4. The weight of the stents could not be a measurable because of        the loss of the drug and uptake of water.    -   5. All test samples were handled with PPE appropriate for drug        containing stents.

Data Summary and Results

Group Total Defects per Stent No primer control 0.00  15 min. bake 0.00 60 min. bake 0.33 240 min. bake 0.00 THF, 15 min. bake 0.00

Example 36 Objective

The objective of this experiment was to test the adhesive properties ofan Actinomycin-D containing coating on stainless steel stents having anEVAL primer layer made from a DMSO:THF solution applied to the stents.The coated stents were tested under wet flow conditions of saline heatedto 37° C. The number of “peel defects” on a select number of stent ringswas observed.

Group Treatment Drying Time (min.) A Argon plasma treatment + EVALprimer 15 B Argon plasma treatment + EVAL primer 30 C Argon plasmatreatment + EVAL primer 60 D Argon plasma treatment + EVAL primer 90 EArgon plasma treatment + EVAL primer 120

Materials and Equipment

1. 10, 13 mm SOLO stents, cleaned ultrasonically in IPA for 15 minutes;

2. 2% EVAL in 1:1 THF:DMSO solution;

3. 10 Balloon catheters or subassemblies to expand the stents;

4. Actinomycin-D solution, 1:1 THF:DMSO with 1:3 Act-D:EVAL, 2% EVAL;

5. 4.0 mm Tecoflex tubing;

6. Saline;

7. Lint Free Wipes SU 00126 or equivalent;

8. 100% IPA;

9. Convection Oven;

10. Timer;

11. Plasma Machine;

12. Ultrasonic cleaner;

13. Mettler balance with 0.1 microgram resolution;

14. Spray/bake mandrels and tips;

15. Flow Meter, N1429;

16. Microscope, minimum magnification 50×;

17. EFD controller with spray apparatus without translational stage; and

18. EFD controller with spray apparatus with translational stage.

Preparation

1. Sonicated the stents in IPA for 15 minutes.2. Weighed each stent to the nearest microgram.3. Prepare the stent samples for each group.

A. Primer Coat

-   -   i. Placed samples on sample holder. Performed argon plasma        treatment.    -   ii. Sprayed the primer layer (2% EVAL, 1:1 THF:DMSO) onto the        stents with translational spray coater. Used 1.5 sec. for the        spray time and speed 7 to achieve 10-40 μg of coating.    -   iii. Baked the stents at 140° C. for the specified time in the        convection oven.    -   iv. Weighed the stents and recorded measurements to the nearest        microgram.

B. Drug Coat

-   -   i. Sprayed the stents with a 3:1, EVAL:Act-D, 2% EVAL, 1:1        DMSO:THF solution for three seconds per pass for three passes.        After each spray pass, dried the stents in the convection oven        for 15 minutes at 50° C.    -   ii. Weighed the stents and recorded measurements. If the drug        coat weight matched the target weight, the stents were returned        to the oven for 240 minutes. If weight gain did not match, the        stents were returned to the glove box for additional spray coat        application. Spray time on subsequent passes was adjusted to        achieve target weight.

4. Wet Flow Test Sample Preparation

-   -   A. Crimped the stents onto the balloon catheters.    -   B. Inflated the stents to 4.0 mm in the Tecoflex tubing with the        balloon catheters—submerged in 37° C. water.    -   C. Disposed Act-D contaminated water as hazardous waste.

Test Method/Procedure

1. Set flow rate at 50 ml/min.2. Performed wet flow testing overnight for about 18 hrs.3. Removed the stents from the Tecoflex tubing with a stent catcher.4. Counted defects, based on the number of peel defects at rings 1, 3,5, 7, and 10 on the stents' OD. Counted defects on the ID of the samerings.5. All test samples were handled with PPE appropriate for drugcontaining stents.

Data Summary and Results

Drying Total Defects Total Defects per Total Defects per Time (min.) perStent Stent (end rings) Stent (middle rings) 15 0.0 0.0 0.0 30 2.0 2.00.0 60 1.0 1.0 0.0 90 0.0 0.0 0.0 120 0.5 0.5 0.0

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects and, therefore, the appended claims areto encompass within their scope all such changes and modifications asfall within the true spirit and scope of this invention.

1. An implantable device comprising a coating, wherein the coatingcomprises: a) a reservoir region comprising a polymer and a drug; and b)a primer region free from any drugs located under the reservoir regionand on the surface of the device, the primer region comprising amaterial selected from a group consisting of poly(hydroxyvalerate),poly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide),poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone,polyorthoesters, polyanhydrides, poly(glycolic acid), poly(D,L-lacticacid), poly(glycolic acid-co-trimethylene carbonate), polyphosphoesters,polyphosphoester urethanes, poly(amino acids), cyanoacrylates,poly(trimethylene carbonates), poly(iminocarbonate),copoly(ether-esters), polyalkylene oxalates, polyphosphazenes, fibrin,fibrinogen, cellulose, starch, collagen, hyaluronic acid, polyurethanes,silicones, polyesters, polyolefins, polyisobutylene,ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers, polyvinyl chloride, polyvinyl ethers,polyvinyl methyl ether, polyvinylidene halides, polyvinylidene fluoride,polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinylaromatics, polystyrene, polyvinyl esters, polyvinyl acetate, copolymersof vinyl monomers with each other and olefins, ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins,ethylene-vinyl acetate copolymers, polyamides, Nylon 66,polycaprolactam, alkyd resins, polycarbonates, polyoxymethylenes,polyimides, polyethers, epoxy resins, rayon, rayon-triacetate,cellulose, cellulose acetate, cellulose butyrate, cellulose acetatebutyrate, cellophane, cellulose nitrate, cellulose propionate, celluloseethers, carboxymethyl cellulose, and combinations or blends thereof. 2.The implantable device of claim 1, wherein the device is a stent.